NOVEL HETEROCYCLIC NF-kB INHIBITORS

ABSTRACT

The present invention relates to compounds of the general formula (II): 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salts thereof with an acid or a base, or pharmaceutically acceptable prodrugs or a stereoisomer thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a divisional of U.S. patent application Ser. No. 11/375,259,filed Mar. 15, 2006, which is a continuation-in-part of U.S. patentapplication Ser. No. 11/192,009, filed Jul. 29, 2005, which in turnclaims priority to U.S. Provisional Application No. 60/612,794, filedSep. 27, 2004. The contents of all applications are incorporated herein,in their entirety, by reference.

FIELD OF THE INVENTION

The present invention relates to compounds of the general formula (I),(Ia), (Ib), (Ic), (II), or (III) or a stereoisomer thereof or possiblepharmaceutically acceptable salts thereof with an acid or a base, orpharmaceutically acceptable prodrugs of these compounds, for use as amedicament. The compounds of the invention are exceptionally useful forthe treatment of diseases associated with abnormal andhyperproliferation of cells in mammals, especially in humans. Inparticular, they are useful for the treatment of diseases characterizedby a hyperproliferation of T-cells.

The present invention relates to compounds which are suitable for thetherapy of diseases that can be treated by modulating cellular pathwaysin eukaryotes, e.g. cancer, immunological or inflammatory disorders, andviral infections, to further processes for the preparation of thesecompounds, and to their use.

T-cell homeostasis is critical for the maintenance of immune tolerance.Defects in T-cell homeostasis can lead to autoimmune pathology.Autoimmune diseases include a large spectrum of clinically distinctentities that share a common aetiology, a misguided, self-directedimmune response.

This immune response can also be the consequence of an organ transplant.

Evidence suggests a prime role of T-cell reactivity in autoimmunediseases. Measuring proliferative responses in T-lymphocytes is a widelyused assay to measure immune competence (Killestein, J. et al. J.Neuroimmunol. 133, 217-24, 2002).

We used a nonradioactive technique for the measurement of in vitroT-cell proliferation (Messele, T. et al. Clinical and DiagnosticLaboratory Immunology 687-692, 2000).

Peripheral blood mononuclear cells (PBMCs) were isolated from humanblood obtained from volunteer donators. PBMCs were isolated bycentrifugation in ACCUSPIN tubes using HISTOPAQUE.

PBMCs were stimulated with PHA and cell proliferation was measured witha Roche calorimetric BromUridin incorporation ELISA kit.

Regulation of the immune response is controlled by a variety ofsignalling pathways such as T-cell or TNF receptor signalling (Chen, G.et al. Science 296, 1634-1635, 2002). To further characterize targets ofcompounds which we found active in the T-cell proliferation assay, wetested the compounds on their ability to inhibit the human proteasome.

The major neutral proteolytic activity in the cytosol and nucleus is theproteasome, a 20S (700 kDa) particle with multiple peptidase activities.The continual turnover of cellular proteins by the ubiquitin-proteasomepathway is used by the immune system to screen for the presence ofabnormal intracellular proteins (Dantuma, N. P. et al. Nat. Biotechnol.2000, 18(5), 538-43; Goldberg, A L. et al. Nature 357, 375, 1993).

The ubiquitin-proteasome pathway plays an essential role in theregulation of NF-κB activity, being responsible for the degradation ofthe inhibitor IκB-α. In order to be targeted for degradation by theproteasome, IκB-α must first undergo selective phosphorylation at serineresidues 32 and 36, followed by ubiquitinylation (Chen, Z J. et al. Cell84, 853-862, 1996; Brown, K. et al. Science 267, 1485, 1995).

NF-κB, a transcription factor, regulates the transcription of animportant set of genes, involved in inflammatory responses (Baeuerle, PA. et al. Cell 87, 1, 13-20, 1996). Proteasome inhibitors block IκB-αdegradation and NF-κB activation (Traeckner et al. EMBO J. 13, 5433,1994).

Patents describing proteasome inhibitors have been described in reviews(Adams, J. et al. Ann. Rev. Med. Chem. 31, 279-288, 1996) and in U.S.Pat. Nos. 6,117,887, 5,834,487, WO 00/004954, WO 00/04954, WO 00/170204,WO 00/33654, WO 00/64863, WO 00/114324, WO 99/15183, WO 99/37666.

Here we describe novel chemical entities with proteasome inhibitoryactivity.

NF-κB (Nuclear Factor-κB) is an eucariotic transcription factor of therel family, which is located in the cyctoplasm in an inactive complex,as a homo- or heterodimer. Predominantly it exists as a heterodimercomposed of p50 and p65 subunits, bound to inhibitory proteins of theIκB family, usually IκB-α (D. Thanos et al., Cell 80, 529, 1995). NF-κBis activated in response to different stimuli, among which inflammatorycytokines, UV radiation, phorbol esters, bacterial and viral infections.Stimulation triggers the release of NF-κB from IκB in consequence of thephosphorylation and the following degradation of the IκB-α protein (P.A. Baeuerle et al., Annu. Rev. Immunol. 12, 141, 1995) by theproteasome. Once it is set free, NF-κB translocates in the nucleus whereit binds to the DNA at specific κB-sites and induces the transcriptionof a variety of genes encoding proteins involved in controlling theimmune and inflammatory responses, amongst others interleukins, TNF-α,the NO-synthase and the cyclooxigenase 2 (S. Grimm et al., J. Biochem.290, 297, 1993). Accordingly, NF-κB is considered an early mediator ofthe immune and inflammatory responses and it is involved in the controlof cell proliferation and in the pathogenesis of various human diseases,such as rheumatoid arthritis (H. Beker et al., Clin. Exp. Immunol. 99,325, 1995), ischemia (A. Salminen et al., Biochem. Biophys. Res. Comm.212, 939, 1995), arteriosclerosis (A. S. Baldwin, Annals Rev. Immunol.212, 649, 1996), as well as in the pathogenesis of AIDS.

Inhibition of NF-κB mediated gene transcription can be accomplishedthrough inhibition of phosphorylation of the inhibitory protein IκB,inhibition of IκB degradation, inhibition of NF-κB (p50/p65) nucleartranslocation, the inhibition of NF-κB-DNA binding or NF-κB-mediated DNAtranscription (J. C. Epinat et al., Oncogene 18, 6896, 1999).

The present invention relates to compounds of the general formula (I) ora salt or a physiologically functional derivative or a stereoisomerthereof,

wherein

-   R¹ is independently hydrogen, alkyl, cycloalkyl, hydroxyalkyl,    haloalkyl, haloalkyloxy, aryl, substituted aryl, heteroaryl,    substituted heteroaryl, arylalkyl or substituted arylalkyl;-   R² is independently —NR³R⁴,

-   R³ is independently alkyl, cycloalkyl, alkoxy, alkylamine, —OH, —SH,    alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or    heteroaryl;-   R⁴ is independently alkyl, cycloalkyl, alkoxy, alkylamine,    alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or    heteroaryl;-   R⁵ is independently H, COR⁶, CO₂R⁶, SOR⁶, SO₂R⁶, SO₃R⁶, alkyl,    cycloalkyl, alkoxy, —NH₂, alkylamine, —NR⁷COR⁶, halogen, —OH, —SH,    alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or    heteroaryl;-   R⁶ is independently H, alkyl, cycloalkyl, —NH₂, alkylamine, aryl or    heteroaryl;-   R⁷ is independently H, alkyl, cycloalkyl, alkoxy, —OH, —SH,    alkylthio, hydroxyalkyl, aryl, or heteroaryl;-   p is 0, or 1;-   q is 0, or 1;-   X is CO or SO₂;

an alkyl group, if not stated otherwise, denotes a linear or branchedC₁-C₆-alkyl, preferably a linear or branched chain of one to five carbonatoms, a linear or branched C₂-C₆-alkenyl or a linear or branchedC₂-C₆-alkinyl group, which can optionally be substituted by one or moresubstituents R′;

the C₁-C₆-alkyl, C₂-C₆-alkenyl and C₂-C₆-alkinyl residue may be selectedfrom the group comprising —CH₃, —C₂H₅, —CH═CH₂, —C≡CH, —C₃H₇, —CH(CH₃)₂,—CH₂—CH═CH₂, —C(CH₃)═CH₂, —CH═CH—CH₃, —C≡C—CH₃, —CH₂—C≡CH, —C₄H₉,—CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅, —C(CH₃)₃, —C₅H₁₁, —C₆H₁₃, —C(R′)₃,—C₂(R′)₅, —CH₂—C(R′)₃, —C₃(R′)₇, —C₂H₄—C(R′)₃, —C₂H₄—CH═CH₂,—CH═CH—C₂H₅, —CH═C(CH₃)₂, —CH₂—CH═CH—CH₃, —CH═CH—CH═CH₂, —C₂H₄—C—CH,—C≡C—C₂H₅, —CH₂—C≡C—CH₃, —C≡C—CH═CH₂, —CH═CH—C≡CH, —C≡C—C—CH,—C₂H₄—CH(CH₃)₂, —CH(CH₃)—C₃H₇, —CH₂—CH(CH₃)—C₂H₅, —CH(CH₃)—CH(CH₃)₂,—C(CH₃)₂—C₂H₅, —CH₂—C(CH₃)₃, —C₃H₆—CH═CH₂, —CH═CH—C₃H₇, —C₂H₄—CH═CH—CH₃,—CH₂—CH═CH—C₂H₅, —CH₂—CH═CH—CH═CH₂, —CH═CH—CH═CH—CH₃, —CH═CH—CH₂—CH═CH₂,—C(CH₃)═CH—CH═CH₂, —CH═C(CH₃)—CH═CH₂, —CH═CH—C(CH₃)═CH₂,—CH₂—CH═C(CH₃)₂, C(CH₃)═C(CH₃)₂, —C₃H₆—C—CH, —C≡C—C₃H₇, —C₂H₄—C≡C—CH₃,—CH₂—C≡C—C₂H₅, —CH₂—C≡C—CH═CH₂, —CH₂—CH═CH—C—CH, —CH₂—C≡C—C≡CH,—C≡C—CH═CH—CH₃, —CH═CH—C≡C—CH₃, —C≡C—C≡C—CH₃, —C≡C—CH₂—CH═CH₂,—CH═CH—CH₂—C—CH, —C≡C—CH₂—C—CH, —C(CH₃)═CH—CH═CH₂, —CH═C(CH₃)—CH═CH₂,—CH═CH—C(CH₃)═CH₂, —C(CH₃)═CH—C—CH, —CH═C(CH₃)—C—CH, —C≡C—C(CH₃)═CH₂,—C₃H₆—CH(CH₃)₂, —C₂H₄—CH(CH₃)—C₂H₅, —CH(CH₃)—C₄H₉, —CH₂—CH(CH₃)—C₃H₇,—CH(CH₃)—CH₂—CH(CH₃)₂, —CH(CH₃)—CH(CH₃)—C₂H₅, —CH₂—CH(CH₃)—CH(CH₃)₂,—CH₂—C(CH₃)₂—C₂H₅, —C(CH₃)₂—C₃H₇, —C(CH₃)₂—CH(CH₃)₂, —C₂H₄—C(CH₃)₃,—CH(CH₃)—C(CH₃)₃, —C₄H₈—CH═CH₂, —CH═CH—C₄H₉, —C₃H₆—CH═CH—CH₃,—CH₂—CH═CH—C₃H₇, —C₂H₄—CH═CH—C₂H₅, —CH₂—C(CH₃)═C(CH₃)₂,—C₂H₄—CH═C(CH₃)₂, —C₄H₈—C—CH, —C≡C—C₄H₉, —C₃H₆—C≡C—CH₃, —CH₂—C≡C—C₃H₇,—C₂H₄—C≡C—C₂H₅;

R′ is independently H, —CO₂R″, —CONHR″, —CR″O, —SO₂NR″,—NR″—CO-haloalkyl, —NO₂, —NR″—SO₂-haloalkyl, —NR″—SO₂-alkyl, —SO₂-alkyl,—NR″—CO-alkyl, —CN, alkyl, cycloalkyl, aminoalkyl, alkylamino, alkoxy,—OH, —SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen,haloalkyl, haloalkyloxy, aryl, arylalkyl or heteroaryl;

R″ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl,heteroaryl or aminoalkyl;

a cycloalkyl group denotes a non-aromatic ring system containing threeto eight carbon atoms, preferably four to eight carbon atoms, whereinone or more of the carbon atoms in the ring can be substituted by agroup E, E being O, S, SO, SO₂, N, or NR″, R″ being as defined above;the C₃-C₈-cycloalkyl residue may be selected from the group comprising-cyclo-C₃H₅, -cyclo-C₄H₇, -cyclo-C₅H₉, -cyclo-C₆H₁₁, -cyclo-C₇H₁₃,-cyclo-C₈H₁₅, morpholine-4-yl, piperazinyl, 1-alkylpiperazine-4-yl;

an alkoxy group denotes an O-alkyl group, the alkyl group being asdefined above; the alkoxy group is preferably a methoxy, ethoxy,isopropoxy, t-butoxy or pentoxy group;

an alkylthio group denotes an S-alkyl group, the alkyl group being asdefined above;

an haloalkyl group denotes an alkyl group which is substituted by one tofive halogen atoms, the alkyl group being as defined above; thehaloalkyl group is preferably a —C(R¹⁰)₃, —CR¹⁰(R^(10′))₂,—CR¹⁰(R^(10′))R^(10″), —C₂(R¹⁰)₅, —CH₂—C(R¹⁰)₃, —CH₂—CR¹⁰(R^(10′))₂,—CH₂—CR¹⁰(R^(10′))R^(10″), —C₃(R¹⁰)₇, or —C₂H₄—C(R¹⁰)₃, wherein R¹⁰,R^(10′) R^(10″) represent F, Cl, Br or I, preferably F;

a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being asdefined above;

an haloalkyloxy group denotes an alkoxy group which is substituted byone to five halogen atoms, the alkyl group being as defined above; thehaloalkyloxy group is preferably a —OC(R¹⁰)₃, —OCR¹⁰(R^(10′))₂,—OCR¹⁰(R^(10′))R^(10″), —OC₂(R¹⁰)₅, —OCH₂—C(R¹⁰)₃, —OCH₂—CR¹⁰(R¹⁰)₂,—OCH₂—CR¹⁰(R^(10′))R^(10″), —OC₃(R¹⁰)₇ or —OC₂H₄—C(R¹⁰)₃, wherein R¹⁰,R^(10′), R^(10″) represent F, Cl, Br or I, preferably F;

a hydroxyalkylamino group denotes an (HO-alkyl)₂-N— group orHO-alkyl-NH— group, the alkyl group being as defined above;

an alkylamino group denotes an HN-alkyl or N-dialkyl group, the alkylgroup being as defined above;

a halogen group is chlorine, bromine, fluorine or iodine;

an aryl group denotes an aromatic group having five to fifteen carbonatoms, which can optionally be substituted by one or more substituentsR′, where R′ is as defined above; the aryl group is preferably a phenylgroup, -o-C₆H₄—R′, -m-C₆H₄—R′, -p-C₆H₄—R′, 1-naphthyl, 2-naphthyl,1-anthracenyl or 2-anthracenyl;

a heteroaryl group denotes a 5- or 6-membered heterocyclic group whichcontains at least one heteroatom like O, N, S. This heterocyclic groupcan be fused to another ring. For example, this group can be selectedfrom a thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl,isothiazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazol-3-yl,1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl,1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,5-thiadiazol-3-yl,1-imidazolyl, 2-imidazolyl, 1,2,5-thiadiazol-4-yl, 4-imidazolyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl,4-pyranyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl,4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl,1H-tetrazol-2-yl, 1H-tetrazol-3-yl, tetrazolyl, 2-indolyl, 3-indolyl,2-indolinyl, 3-indolinyl, benzo[b]furanyl, benzo[b]thiophenyl,benzimidazolyl, benzothiazolyl, quinazolinyl, quinoxazolinyl,quinolinyl, tetrahydroquinolinyl, isoquinolinyl,tetrahydro-thieno[3,4-d]imidazol-2-one, pyrazolo[5,1-c][1,2,4]triazine,or tetrahydroisoquinolinyl group. This heterocyclic group can optionallybe substituted by one or more substituents R′, wherein R′ is as definedabove.

The invention also provides a pharmaceutical composition comprising acompound of formula (I), in free form or in the form of pharmaceuticallyacceptable salts and physiologically functional derivatives, togetherwith a pharmaceutically acceptable diluent or carrier therefore.

The term “physiologically functional derivative” as used herein refersto compounds which are not pharmaceutically active themselves but whichare transformed into their pharmaceutical active form in vivo, i.e. inthe subject to which the compound is administered. Examples ofphysiologically functional derivatives are prodrugs.

In addition, the present invention provides methods for preparing thecompounds of the invention such as compounds of formula (I).

The compounds of formula (I) may be obtained via various methods.

Piperidin-4-yl-thiazole-4-carboxamide can be prepared by various methodsdescribed in the literature. One such example is the oxidation of theappropriate 2,5-dihydrothiazoles as described in Houben-Weyl, 2002, 730.The dihydrothiazoles can also synthesised by methods described in thesame reference or described in You, S., Razavi, H., Kelly, J. W. Angew.Chem. 2003, 115, 87 or Katritzky, A R., Cai, C., Suzuki, K., Singh, S K.J. Org. Chem. 2004, 69, 811-814 and references in both papers.Alternative methods were described by Yasuchika, S. et. al.Heterocycles, Vol. 57, No. 5, 2002.

In a preferred embodiment of the invention, in the compounds of formula(I), R¹ is:

In a preferred embodiment of the invention, in the compounds of formula(I), R⁵ is:

In another preferred embodiment, in the compounds of formula (I), R³, R⁴and R⁷ is H.

In a preferred embodiment of the invention, in the compounds of formula(I), R² is:

In a preferred embodiment of the invention, in the compounds of formula(I), R¹ is substituted aryl, p is 0, q is 1, X is CO, and R² is

In a preferred embodiment of the invention, in the compounds of formula(I), R¹ is benzyl, p is 0, q is 0, and R² is

The present invention relates to compounds of the general formula (Ia)or a pharmaceutically acceptable salts thereof with an acid or a base,or pharmaceutically acceptable prodrugs or a stereoisomer thereof,

wherein

-   R is independently hydrogen, alkyl, cycloalkyl, hydroxyalkyl,    haloalkyl, haloalkyloxy, aryl, or heteroaryl;-   R¹ is independently alkyl, cycloalkyl, hydroxyalkyl, haloalkyl,    haloalkyloxy, aryl, or heteroaryl;-   X is CO, CS or SO₂;-   Y is CO, CS or SO₂;-   Z is NR², S, or O;-   R^(2′) is H, alkyl, —C(O)NR⁷, —C(O)R^(e), cycloalkyl, haloalkyl,    hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl;-   R^(c) is independently H, OH, SH, NROR¹, NH₂, alkylamino,    hydroxyalkylamino, halogen, CONR^(d)R^(e), alkoxy, alkyl,    cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or    heteroaryl;-   R^(d) is H, halogen, alkyl, —C(NR⁷)NR^(7′)R⁸, —(CH₂)_(p)aryl,    —(CH₂)_(p)NR⁷R⁸, —C(O)NR⁷R⁸, —N═CR⁷R⁸, —NR⁷C(O)R⁸, cycloalkyl,    haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl    or aryl;-   R⁷, R^(7′) independently represent H, alkyl, cycloalkyl, haloalkyl,    hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;-   R⁸ is H, NH₂, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl,    hydroxyalkylamino, alkylamino, heteroaryl or aryl;-   R^(e) independently represents H, —CN, —OH, —SH, —CO₂R^(4′),    —C(O)R^(4′), —SO₂NR^(4′), —NR^(4′)R^(5′), —C(O)NR⁷R⁸, —SO₂-alkyl,    —SO₂R^(4′), SO₃R^(4′), —N═CR^(4′)R^(5′), —NR^(4′)C(O)R^(4″),    —NR^(4′)—CO-haloalkyl, —NO₂, —NR^(4′)—SO₂-haloalkyl,    —NR^(4′)—SO₂-alkyl, —NR^(4′)—CO-alkyl, —NR^(4′)(CH₂)_(p)heteroaryl,    alkyl, hydroxyalkyl, cycloalkyl, alkylamino, aryl hydroxyalkylamino,    alkoxy, alkylthio, —O(CH₂)_(p)[O(CH₂)_(p)]_(q)OCH₃,    —C(NR⁴)NR^(4′)-benzimidazolyl, —C(NR^(4″))NR^(4′)benzthiazolyl,    —C(NR^(4″))NR^(4′)benz-oxazolyl, or heteroaryl;-   R^(4′), R^(4″), R^(5′) independently represent H, alkyl, cycloalkyl,    haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino,    —C(NR⁷)NR^(7′)R⁸, —(CH₂)_(p)aryl, —(CH₂)_(p)NR⁷R⁸, —C(O)NR⁷R⁸,    —N═CR⁷R⁸, —NR⁷C(O)R⁸, halogen, heteroaryl, or aryl-   p is 1 to 6;-   q is 1 to 6;-   R² is independently

-   R⁵ is independently H, COR⁶, CO₂R⁶, SOR⁶, SO₂R⁶, SO₃R⁶, alkyl,    cycloalkyl, alkoxy, —NH₂, alkylamine, —NR⁷COR⁶, halogen, —OH, —SH,    alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or    heteroaryl;-   R⁶ is independently H, alkyl, cycloalkyl, amino, haloalkyl,    hydroxyalkyl, hydroxyalkylamino, alkylamino, aryl or heteroaryl;

an alkyl group, if not stated otherwise, denotes a linear or branchedC₁-C₆-alkyl, preferably a linear or branched chain of one to five carbonatoms, a linear or branched C₂-C₆-alkenyl or a linear or branchedC₂-C₆-alkinyl group, which can optionally be substituted by one or moresubstituents R′;

the C₁-C₆-alkyl, C₂-C₆-alkenyl and C₂-C₆-alkinyl residue may be selectedfrom the group comprising —CH₃, —C₂H₅, —CH═CH₂, —C—CH, —C₃H₇, —CH(CH₃)₂,—CH₂—CH═CH₂, —C(CH₃)═CH₂, —CH═CH—CH₃, —C≡C—CH₃, —CH₂—C—CH, —C₄H₉,—CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅, —C(CH₃)₃, —C₅H₁₁, —C₆H₁₃, —C(R′)₃,—C₂(R′)₅, —CH₂—C(R′)₃, —C₃(R′)₇, —C₂H₄—C(R′)₃, —C₂H₄—CH═CH₂,—CH═CH—C₂H₅, —CH═C(CH₃)₂, —CH₂—CH═CH—CH₃, —CH═CH—CH═CH₂, —C₂H₄—C—CH,—C≡C—C₂H₅, —CH₂—C≡C—CH₃, —C≡C—CH═CH₂, —CH═CH—C—CH, —C≡C—C≡CH,—C₂H₄—CH(CH₃)₂, —CH(CH₃)—C₃H₇, —CH₂—CH(CH₃)—C₂H₅, —CH(CH₃)—CH(CH₃)₂,—C(CH₃)₂—C₂H₅, —CH₂—C(CH₃)₃, —C₃H₆—CH═CH₂, —CH═CH—C₃H₇, —C₂H₄—CH═CH—CH₃,—CH₂—CH═CH—C₂H₅, —CH₂—CH═CH—CH═CH₂, —CH═CH—CH═CH—CH₃, —CH═CH—CH₂—CH═CH₂,—C(CH₃)═CH—CH═CH₂, —CH═C(CH₃)—CH═CH₂, —CH═CH—C(CH₃)═CH₂,—CH₂—CH═C(CH₃)₂, C(CH₃)═C(CH₃)₂, —C₃H₆—C—CH, —C≡C—C₃H₇, —C₂H₄—C≡C—CH₃,—CH₂—C≡C—C₂H₅, —CH₂—C≡C—CH═CH₂, —CH₂—CH═CH—C—CH, —CH₂—C≡C—C≡CH,—C≡C—CH═CH—CH₃, —CH═CH—C≡C—CH₃, —C≡C—C≡C—CH₃, —C≡C—CH₂—CH═CH₂,—CH═CH—CH₂—C—CH, —C≡C—CH₂—C—CH, —C(CH₃)═CH—CH═CH₂, —CH═C(CH₃)—CH═CH₂,—CH═CH—C(CH₃)═CH₂, —C(CH₃)═CH—C—CH, —CH═C(CH₃)—C—CH, —C≡C—C(CH₃)═CH₂,—C₃H₆—CH(CH₃)₂, —C₂H₄—CH(CH₃)—C₂H₅, —CH(CH₃)—C₄H₉, —CH₂—CH(CH₃)—C₃H₇,—CH(CH₃)—CH₂—CH(CH₃)₂, —CH(CH₃)—CH(CH₃)—C₂H₅, —CH₂—CH(CH₃)—CH(CH₃)₂,—CH₂—C(CH₃)₂—C₂H₅, —C(CH₃)₂—C₃H₇, —C(CH₃)₂—CH(CH₃)₂, —C₂H₄—C(CH₃)₃,—CH(CH₃)—C(CH₃)₃, —C₄H₈—CH═CH₂, —CH═CH—C₄H₉, —C₃H₆—CH═CH—CH₃,—CH₂—CH═CH—C₃H₇, —C₂H₄—CH═CH—C₂H₅, —CH₂—C(CH₃)═C(CH₃)₂,—C₂H₄—CH═C(CH₃)₂, —C₄H₈—C—CH, —C≡C—C₄H₉, —C₃H₆—C≡C—CH₃, —CH₂—C≡C—C₃H₇,—C₂H₄—C≡C—C₂H₅;

R′ is independently H, —CO₂R″, —CONHR″, —CR″O, —SO₂NR″,—NR″—CO-haloalkyl, —NO₂, —NR″—SO₂-haloalkyl, —NR″—SO₂-alkyl, —SO₂-alkyl,—NR″—CO-alkyl, —CN, alkyl, cycloalkyl, alkylamino, alkoxy, —OH, —SH,alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl,haloalkyloxy, aryl, or heteroaryl;

R″ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl,or heteroaryl;

a cycloalkyl group denotes a non-aromatic ring system containing threeto eight carbon atoms, preferably four to eight carbon atoms, whereinone or more of the carbon atoms in the ring can be substituted by agroup E, E being O, S, SO, SO₂, N, or NR″, R″ being as defined above;the C₃-C₈-cycloalkyl residue may be selected from the group comprising-cyclo-C₃H₅, -cyclo-C₄H₇, -cyclo-C₅H₉, -cyclo-C₆H₁₁, -cyclo-C₇H₁₃,-cyclo-C₈H₁₅, morpholine-4-yl, piperazinyl, 1-alkylpiperazine-4-yl;

an alkoxy group denotes an O-alkyl group, the alkyl group being asdefined above; the alkoxy group is preferably a methoxy, ethoxy,isopropoxy, t-butoxy or pentoxy group;

an alkylthio group denotes an S-alkyl group, the alkyl group being asdefined above;

an haloalkyl group denotes an alkyl group which is substituted by one tofive halogen atoms, the alkyl group being as defined above; thehaloalkyl group is preferably a —C(R¹⁰)₃, —CR¹⁰(R^(10′))₂,—CR¹⁰(R^(10′))R^(10″), —C₂(R¹⁰)₅, —CH₂—C(R¹⁰)₃, —CH₂—CR¹⁰(R^(10′))₂,—CH₂—CR¹⁰(R^(10′))R^(10″), —C₃(R¹⁰)₇, or —C₂H₄—C(R¹⁰)₃, wherein R¹⁰,R^(10′), R^(10″) represent F, Cl, Br or I, preferably F;

a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being asdefined above;

an haloalkyloxy group denotes an alkoxy group which is substituted byone to five halogen atoms, the alkyl group being as defined above; thehaloalkyloxy group is preferably a —OC(R¹⁰)₃, —OCR¹⁰(R^(10′))₂,—OCR¹⁰(R^(10′))R^(10″), —OC₂(R¹⁰)₅, —OCH₂—C(R¹⁰)₃, —OCH₂—CR¹⁰(R¹⁰)₂,—OCH₂—CR¹⁰(R^(10′))R^(10″), —OC₃(R¹⁰)₇ or —OC₂H₄—C(R¹⁰)₃, wherein R¹⁰,R^(10′), R^(10″) represent F, Cl, Br or I, preferably F;

a hydroxyalkylamino group denotes an (HO-alkyl)₂-N— group orHO-alkyl-NH— group, the alkyl group being as defined above;

an alkylamino group denotes an HN-alkyl or N-dialkyl group, the alkylgroup being as defined above;

a halogen group is chlorine, bromine, fluorine or iodine;

an aryl group denotes an aromatic group having five to fifteen carbonatoms, which can optionally be substituted by one or more substituentsR′, where R′ is as defined above; the aryl group is preferably a benzylgroup, a phenyl group, -o-C₆H₄—R′, -m-C₆H₄—R′, -p-C₆H₄—R′, 1-naphthyl,2-naphthyl, 1-anthracenyl or 2-anthracenyl;

a heteroaryl group denotes a 5- or 6-membered heterocyclic group whichcontains at least one heteroatom selected from O, N, and S. Thisheterocyclic group can be fused to another aromatic ring. For example,this group can be selected from a thiadiazole, thiazol-2-yl,thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl,isothiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isooxazol-3-yl,isooxazol-4-yl, isooxazol-5-yl, benzooxazol-2-yl, benzooxazol-4-yl,benzooxazol-5-yl, benzoisooxazol-3-yl, benzoisooxazol-4-yl,benzoisooxazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl,1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,4-thiadiazol-3-yl,1,2,4-thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl,isothiazol-5-yl, benzoisothiazol-3-yl, benzoisothiazol-4-yl,benzoisothiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl,1,2,5-thiadiazol-4-yl, 4-imidazolyl, benzoimidazol-4-yl, 1-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 4-pyranyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl,2,4-dimethoxy-6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl,1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1,2,3-triazol-4-yl,1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl,1,3,5-triazol-6-yl, 2,4-dimethoxy-1,3,5-triazol-6-yl, 1H-tetrazol-2-yl,1H-tetrazol-3-yl, tetrazolyl, acridyl, furazane, indazolyl, phenazinyl,carbazolyl, phenoxazinyl, indolizine, 2-indolyl, 3-indolyl, 4-indolyl,5-indolyl, 6-indolyl, 7-indolyl, 1-isoindolyl, 3-isoindolyl,4-isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-indolinyl,3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl,benzo[b]furanyl, benzofurazane, benzothiofurazane, benzotriazol-1-yl,benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl,benzotriazol-7-yl, benzotriazine, benzo[b]thiophenyl, benzimidazol-2-yl,1H-benzimidazolyl, benzimidazol-4-yl, benzimidazol-5-yl,benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, quinazolinyl,quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl,isoquinolinyl, tetrahydro-isoquinolinyl, purine, phthalazine, pteridine,thiatetraazaindene, thiatriazaindene, isothiazolopyrazine,isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine,tetra-hydrothieno[3,4-d]imidazol-2-one, pyrazolo[5,1-c][1,2,4]triazine,2,3-dihydrobenzo[1,4]-dioxin-2-yl, 2,3-dihydrobenzo[1,4]-dioxin-3-yl,2,3-dihydrobenzo[1,4]-dioxin-5-yl, 2,3-dihydrobenzo[1,4]-dioxin-6-yl,2,6-dimethoxypyrimidin-3-yl, 2,6-dimethoxypyrimidin-4-yl,imidazopyridazine, imidazopyrimidine, imidazopyridine,imidazolotriazine, triazolotriazine, triazolopyridine, triazolopyrazine,triazolopyrimidine, or 4-[1,2,4]triazolo[4,3-a]pyridin-3-yl,1-furo[2,3-c]pyridin-4-yl, 1-furo[2,3-c]pyridin-5-yl,1-furo[2,3-c]pyridin-3-yl, and triazolopyridazine group. Thisheterocyclic group can be substituted by one or more substituents R′,wherein R′ is as defined above.

The present invention relates to compounds of the general formula (Ib)or pharmaceutically acceptable salts thereof with an acid or a base, orpharmaceutically acceptable prodrugs or a stereoisomer thereof,

wherein

-   R¹ is —C(O)R⁷, —C(O)CHR⁷R⁸, —C(O)NR⁷R⁸, —C(O)OR⁷, —R⁷C(O)R⁸, or    —C(S)R⁷;-   R⁹ independently represents H, —CN, —OH, —SH, —CO₂R^(4′), —C(O)R⁴,    —SO₂NR⁴, —NR^(4′)R^(5′), —C(O)NR⁷R⁸, —SO₂-alkyl, —SO₂R^(4′),    SO₃R^(4′), —N═CR^(4′)R^(5′), —NR^(4′)C(O)R^(4″),    —NR^(4′)—CO-haloalkyl, —NO₂, —NR^(4′)—SO₂-haloalkyl,    —NR^(4′)—SO₂-alkyl, —NR^(4′)—CO-alkyl, —NR^(4′)(CH₂)_(p)heteroaryl,    alkyl, hydroxyalkyl, cycloalkyl, alkylamino, aryl hydroxyalkylamino,    alkoxy, alkylthio, —O(CH₂)_(p)[O(CH₂)_(p)]_(q)OCH₃,    —C(NR⁴)NR^(4′)-benzimidazolyl, —C(NR^(4″))NR^(4′)benzthiazolyl,    —C(NR^(4″))NR^(4′)benzoxazolyl, —(CH₂)_(p)NR⁷COR⁸, or heteroaryl;-   R⁴ is H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl,    hydroxyalkylamino, alkylamino, heteroaryl, aryl,-   or R¹ and R⁴ together with the X to which they are attached form a 3    to 8 membered saturated or at least partially unsaturated monocyclic    or polycyclic ring system, wherein at least one ring atom is a    heteroatom selected from O, N, and S, and the ring optionally has    one or more substituents R⁹;-   X is N, or CR²⁺;-   Y is CO, CS or SO₂;-   Z is NR², S, or O;-   R^(2″) is H, alkyl, —C(O)NR⁷, —C(O)R^(e), cycloalkyl, haloalkyl,    hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl;-   R^(2′) is H, alkyl, —C(O)NR^(4′), —C(O)R^(4′), cycloalkyl,    haloalkyl, hydroxyalkyl, hydroxy-alkylamino, alkylamino, heteroaryl,    or aryl;-   R^(4′), R^(4″), R^(5′) independently represent H, alkyl, cycloalkyl,    haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino,    —C(NR⁷)NR^(7′)R⁸, —(CH₂)_(p)aryl, —CH₂)_(p)NR⁷R⁸, —C(O)NR⁷R⁸,    —N═CR⁷R⁸, —NR⁷C(O)R⁸, halogen, heteroaryl, or aryl-   p is 1 to 6;-   q is 1 to 6;-   R^(a) is independently H, OH, SH, NH₂, alkyl, cycloalkyl,    hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino,    hydroxyalkylamino, halogen, aryl, or heteroaryl;-   R^(b) is independently H, OH, SH, NH₂, alkyl, cycloalkyl,    hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino,    hydroxyalkylamino, halogen, aryl, or heteroaryl;-   R^(c) is independently H, OH, SH, NR^(4′)OR^(5′), NH₂, alkylamino,    hydroxyalkylamino, halogen, CONR^(d)R^(e), alkoxy, alkyl,    cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or    heteroaryl;-   R^(d) is H, halogen, alkyl, —C(NR⁷)NR^(7′)R⁸, —(CH₂)_(p)aryl,    —(CH₂)_(p)NR⁷R⁸, —C(O)NR⁷R⁸, —N═CR⁷R⁸, —NR⁷C(O)R⁸, cycloalkyl,    haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl    or aryl;-   R⁷, R^(7′) independently represent H, alkyl, cycloalkyl, haloalkyl,    hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;-   R⁸ is H, NH₂, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl,    hydroxyalkylamino, alkylamino, heteroaryl or aryl;-   R^(e) independently represents H, —CN, —OH, —SH, —CO₂R^(4′),    —C(O)R^(4′), —SO₂NR^(4′), —NR^(4′)R^(5′), —C(O)NR⁷R⁸, —SO₂-alkyl,    —SO₂R^(4′), SO₃R^(4′), —N═CR^(4′)R^(5′), —NR^(4′)C(O)R^(4″),    —NR^(4′)—CO-haloalkyl, —NO₂, —NR^(4′)—SO₂-haloalkyl,    —NR^(4′)—SO₂-alkyl, —NR^(4′)—CO-alkyl, —NR^(4′)(CH₂)_(p)heteroaryl,    alkyl, hydroxyalkyl, cycloalkyl, alkylamino, hydroxy-alkylamino,    alkoxy, alkylthio, —O(CH₂)_(p)[O(CH₂)_(p)]_(q)OCH₃,    —C(NR^(4″))NR^(4′)benz-imidazolyl, —C(NR^(4″))NR^(4′)benzthiazolyl,    —C(NR^(4″))NR^(4′)benzoxazolyl, aryl or heteroaryl;-   R² is independently

-   A is N, O, or CR²;-   R⁵ is independently H, SOR⁷, SO₂R⁷, SO₃R⁷, —C(O)R⁷, —C(O)CHR⁷R⁸,    —C(O)NR⁷R⁸, —C(O)OR⁷, —R⁷C(O)R⁸, —C(S)R⁷, —C(NR⁷)NR^(7′)R⁸,    —(CH₂)_(p)aryl, —(CH₂)_(p)NR⁷R⁸, —C(O)NR⁷R⁸, —N═CR⁷R⁸,    —NR⁷C(O)R^(7′), alkyl, cycloalkyl, alkoxy, —NH₂, alkylamino,    hydroxyalkylamino, halogen, —OH, —SH, alkylthio, hydroxyalkyl,    haloalkyl, haloalkyloxy, aryl or heteroaryl;-   n is 0 to 2;

an alkyl group, if not stated otherwise, denotes a linear or branchedC₁-C₆-alkyl, preferably a linear or branched chain of one to five carbonatoms, a linear or branched C₂-C₆-alkenyl or a linear or branchedC₂-C₆-alkinyl group, which can optionally be substituted by one or moresubstituents R′;

the C₁-C₆-alkyl, C₂-C₆-alkenyl and C₂-C₆-alkinyl residue may be selectedfrom the group comprising —CH₃, —C₂H₅, —CH═CH₂, —C—CH, —C₃H₇, —CH(CH₃)₂,—CH₂—CH═CH₂, —C(CH₃)═CH₂, —CH═CH—CH₃, —C≡C—CH₃, —CH₂—C—CH, —C₄H₉,—CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅, —C(CH₃)₃, —C₅H₁₁, —C₆H₁₃, —C(R′)₃,—C₂(R′)₅, —CH₂—C(R′)₃, —C₃(R′)₇, —C₂H₄—C(R′)₃, —C₂H₄—CH═CH₂,—CH═CH—C₂H₅, —CH═C(CH₃)₂, —CH₂—CH═CH—CH₃, —CH═CH—CH═CH₂, —C₂H₄—C—CH,—C≡C—C₂H₅, —CH₂—C≡C—CH₃, —C≡C—CH═CH₂, —CH═CH—C—CH, —C≡C—C≡CH,—C₂H₄—CH(CH₃)₂, —CH(CH₃)—C₃H₇, —CH₂—CH(CH₃)—C₂H₅, —CH(CH₃)—CH(CH₃)₂,—C(CH₃)₂—C₂H₅, —CH₂—C(CH₃)₃, —C₃H₆—CH═CH₂, —CH═CH—C₃H₇, —C₂H₄—CH═CH—CH₃,—CH₂—CH═CH—C₂H₅, —CH₂—CH═CH—CH═CH₂, —CH═CH—CH═CH—CH₃, —CH═CH—CH₂—CH═CH₂,—C(CH₃)═CH—CH═CH₂, —CH═C(CH₃)—CH═CH₂, —CH═CH—C(CH₃)═CH₂,—CH₂—CH═C(CH₃)₂, C(CH₃)═C(CH₃)₂, —C₃H₆—C—CH, —C≡C—C₃H₇, —C₂H₄—C≡C—CH₃,—CH₂—C≡C—C₂H₅, —CH₂—C≡C—CH═CH₂, —CH₂—CH═CH—C—CH, —CH₂—C≡C—C≡CH,—C≡C—CH═CH—CH₃, —CH═CH—C≡C—CH₃, —C≡C—C≡C—CH₃, —C≡C—CH₂—CH═CH₂,—CH═CH—CH₂—C≡CH, —C≡C—CH₂—C—CH, —C(CH₃)═CH—CH═CH₂, —CH═C(CH₃)—CH═CH₂,—CH═CH—C(CH₃)═CH₂, —C(CH₃)═CH—C—CH, —CH═C(CH₃)—C—CH, —C≡C—C(CH₃)═CH₂,—C₃H₆—CH(CH₃)₂, —C₂H₄—CH(CH₃)—C₂H₅, —CH(CH₃)—C₄H₉, —CH₂—CH(CH₃)—C₃H₇,—CH(CH₃)—CH₂—CH(CH₃)₂, —CH(CH₃)—CH(CH₃)—C₂H₅, —CH₂—CH(CH₃)—CH(CH₃)₂,—CH₂—C(CH₃)₂—C₂H₅, —C(CH₃)₂—C₃H₇, —C(CH₃)₂—CH(CH₃)₂, —C₂H₄—C(CH₃)₃,—CH(CH₃)—C(CH₃)₃, —C₄H₈—CH═CH₂, —CH═CH—C₄H₉, —C₃H₆—CH═CH—CH₃,—CH₂—CH═CH—C₃H₇, —C₂H₄—CH═CH—C₂H₅, —CH₂—C(CH₃)═C(CH₃)₂,—C₂H₄—CH═C(CH₃)₂, —C₄H₈—C—CH, —C≡C—C₄H₉, —C₃H₆—C≡C—CH₃, —CH₂—C≡C—C₃H₇,—C₂H₄—C≡C—C₂H₅;

R′ is independently H, —CO₂R″, —CONHR″, —CR″O, —SO₂NR″,—NR″—CO-haloalkyl, —NO₂, —NR″—SO₂-haloalkyl, —NR″—SO₂-alkyl, —SO₂-alkyl,—NR″—CO-alkyl, —CN, alkyl, cycloalkyl, alkylamino, alkoxy, —OH, —SH,alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl,haloalkyloxy, aryl, or heteroaryl;

R″ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl,or heteroaryl;

a cycloalkyl group denotes a non-aromatic ring system containing threeto eight carbon atoms, preferably four to eight carbon atoms, whereinone or more of the carbon atoms in the ring can be substituted by agroup E, E being O, S, SO, SO₂, N, or NR″, R″ being as defined above;the C₃-C₈-cycloalkyl residue may be selected from the group comprising-cyclo-C₃H₅, -cyclo-C₄H₇, -cyclo-C₅H₉, -cyclo-C₆H₁₁, -cyclo-C₇H₁₃,-cyclo-C₈H₁₅, morpholine-4-yl, piperazinyl, 1-alkylpiperazine-4-yl;

an alkoxy group denotes an O-alkyl group, the alkyl group being asdefined above; the alkoxy group is preferably a methoxy, ethoxy,isopropoxy, t-butoxy or pentoxy group;

an alkylthio group denotes an S-alkyl group, the alkyl group being asdefined above;

an haloalkyl group denotes an alkyl group which is substituted by one tofive halogen atoms, the alkyl group being as defined above; thehaloalkyl group is preferably a —C(R¹⁰)₃, —CR¹⁰(R^(10′))₂,—CR¹⁰(R^(10′))R^(10″), —C₂(R¹⁰)₅, —CH₂—C(R¹⁰)₃, —CH₂—CR¹⁰(R^(10′))₂,—CH₂—CR¹⁰(R^(10′))R^(10″), —C₃(R¹⁰)₇, or —C₂H₄—C(R¹⁰)₃, wherein R¹⁰,R^(10′), R^(10″) represent F, Cl, Br or I, preferably F;

a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being asdefined above;

an haloalkyloxy group denotes an alkoxy group which is substituted byone to five halogen atoms, the alkyl group being as defined above; thehaloalkyloxy group is preferably a —OC(R¹⁰)₃, —OCR¹⁰(R^(10′))₂,—OCR¹⁰(R^(10′))R^(10″), —OC₂(R¹⁰)₅, —OCH₂—C(R¹⁰)₃, —OCH₂—CR¹⁰(R¹⁰)₂,—OCH₂—CR¹⁰(R^(10′))R^(10″), —OC₃(R¹⁰)₇ or —OC₂H₄—C(R¹⁰)₃, wherein R¹⁰,R^(10′), R^(10″) represent F, Cl, Br or I, preferably F;

a hydroxyalkylamino group denotes an (HO-alkyl)₂-N— group orHO-alkyl-NH— group, the alkyl group being as defined above;

an alkylamino group denotes an HN-alkyl or N-dialkyl group, the alkylgroup being as defined above;

a halogen group is chlorine, bromine, fluorine or iodine;

an aryl group denotes an aromatic group having five to fifteen carbonatoms, which can optionally be substituted by one or more substituentsR′, where R′ is as defined above; the aryl group is preferably a benzylgroup, a phenyl group, -o-C₆H₄—R′, -m-C₆H₄—R′, -p-C₆H₄—R′, 1-naphthyl,2-naphthyl, 1-anthracenyl or 2-anthracenyl;

a heteroaryl group denotes a 5- or 6-membered heterocyclic group whichcontains at least one heteroatom selected from O, N, and S. Thisheterocyclic group can be fused to another aromatic ring. For example,this group can be selected from a thiadiazole, thiazol-2-yl,thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl,isothiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isooxazol-3-yl,isooxazol-4-yl, isooxazol-5-yl, benzooxazol-2-yl, benzooxazol-4-yl,benzooxazol-5-yl, benzoisooxazol-3-yl, benzoisooxazol-4-yl,benzoisooxazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl,1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,4-thiadiazol-3-yl,1,2,4-thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl,isothiazol-5-yl, benzoisothiazol-3-yl, benzoisothiazol-4-yl,benzoisothiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl,1,2,5-thiadiazol-4-yl, 4-imidazolyl, benzoimidazol-4-yl, 1-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 4-pyranyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl,2,4-dimethoxy-6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl,1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1,2,3-triazol-4-yl,1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl,1,3,5-triazol-6-yl, 2,4-dimethoxy-1,3,5-triazol-6-yl, 1H-tetrazol-2-yl,1H-tetrazol-3-yl, tetrazolyl, acridyl, furazane, indazolyl, phenazinyl,carbazolyl, phenoxazinyl, indolizine, 2-indolyl, 3-indolyl, 4-indolyl,5-indolyl, 6-indolyl, 7-indolyl, 1-isoindolyl, 3-isoindolyl,4-isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-indolinyl,3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl,benzo[b]furanyl, benzofurazane, benzothiofurazane, benzotriazol-1-yl,benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl,benzotriazol-7-yl, benzotriazine, benzo[b]thiophenyl, benzimidazol-2-yl,1H-benzimidazolyl, benzimidazol-4-yl, benz-imidazol-5-yl,benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, quinazolinyl,quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl,isoquinolinyl, tetrahydro-isoquinolinyl, purine, phthalazine, pteridine,thiatetraazaindene, thiatriazaindene, iso-thiazolopyrazine,isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine,tetrahydro-thieno[3,4-d]imidazol-2-one, pyrazolo[5,1-c][1,2,4]triazine,imidazopyridazine, imidazo-pyrimidine, imidazopyridine,imidazolotriazine, triazolotriazine, 2,3-dihydrobenzo[1,4]-dioxin-2-yl,2,3-dihydrobenzo[1,4]-dioxin-3-yl, 2,3-dihydrobenzo[1,4]-dioxin-5-yl,2,3-dihydrobenzo[1,4]-dioxin-6-yl, 2,6-dimethoxypyrimidin-3-yl,2,6-dimethoxypyrimidin-4-yl, triazolopyridine, triazolopyrazine,triazolopyrimidine, 4-[1,2,4]triazolo[4,3-a]pyridin-3-yl,1-furo[2,3-c]pyridin-4-yl, 1-furo[2,3-c]pyridin-5-yl,1-furo[2,3-c]pyridin-3-yl, and triazolopyridazine group. Thisheterocyclic group can be substituted by one or more substituents R′,wherein R′ is as defined above.

The present invention relates to compounds of the general formula (Ic)or pharmaceutically acceptable salts thereof with an acid or a base, orpharmaceutically acceptable prodrugs or a stereoisomer thereof,

wherein

-   R¹ independently represents H, alkyl, cycloalkyl, hydroxyalkyl,    haloalkyl, haloalkyloxy, aryl, or heteroaryl;-   X is CO, CS or SO₂;-   Y is CO, CS or SO₂;-   Z is NR², S, or O;-   R^(2″) is H, alkyl, —C(O)NR⁷, —C(O)R^(e), cycloalkyl, haloalkyl,    hydroxyalkyl, hydroxy-alkylamino, alkylamino, heteroaryl, or aryl;-   R^(4′), R^(4″), R^(5′) independently represent H, alkyl, cycloalkyl,    haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino,    —C(NR⁷)NR^(7′)R⁸, —(CH₂)_(p)aryl, —(CH₂)_(p)NR⁷R⁸, —C(O)NR⁷R⁸,    —N═CR⁷R⁸, —NR⁷C(O)R⁸, halogen, heteroaryl, or aryl-   p is 1 to 6;-   q is 1 to 6;-   m is 0 to 4;-   r is 0, or 1;-   t is 0, or 1;-   s is 0, or 1;-   R^(b) is independently H, OH, SH, NR^(4′)OR^(5′), NH₂, alkylamino,    hydroxyalkylamino, halogen, CONR^(d)R^(e), alkoxy, alkyl,    cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or    heteroaryl;-   R^(c) is independently H, OH, SH, NR^(4′) OR^(5′), NH₂, alkylamino,    hydroxyalkylamino, halogen, CONR^(d)R^(e), alkoxy, alkyl,    cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or    heteroaryl;-   R^(d) is H, halogen, alkyl, —C(NR⁷)NR^(7′)R⁸, —(CH₂)_(p)aryl,    —(CH₂)_(p)NR⁷R⁸, —C(O)NR⁷R⁸, —N═CR⁷R⁸, —NR⁷C(O)R⁸, cycloalkyl,    haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl    or aryl;-   R⁷, R^(7′) independently represent H, alkyl, cycloalkyl, haloalkyl,    hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;-   R⁸ is H, NH₂, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl,    hydroxyalkylamino, alkylamino, heteroaryl or aryl;-   R^(e) independently represents H, —CN, —OH, —SH, —CO₂R^(4′),    —C(O)R^(4′), —SO₂NR^(4′), —NR^(4′)R^(5′), —C(O)NR⁷R⁸, —SO₂-alkyl,    —SO₂R^(4′), SO₃R^(4′), —N═CR^(4′)R^(5′), —NR^(4′)C(O)R^(4″),    —NR^(4′)—CO-haloalkyl, —NO₂, —NR^(4′)—SO₂-haloalkyl,    —NR^(4′)—SO₂-alkyl, —NR^(4′)—CO-alkyl, —NR^(4′)(CH₂)_(p)heteroaryl,    alkyl, hydroxyalkyl, cycloalkyl, alkylamino, hydroxyalkyl-amino,    alkoxy, alkylthio, —O(CH₂)_(p)[O(CH₂)_(p)]_(q)OCH₃,    —C(NR^(4″))NR^(4′)benz-imidazolyl, —C(NR^(4″))NR^(4′)benzthiazolyl,    —C(NR^(4″))NR^(4′)benz-oxazolyl, aryl or heteroaryl;-   R³ is independently H, OH, SH, NR^(4′)OR^(5′), NH₂,    hydroxyalkylamino, alkylamino, halogen, CONR^(d)R^(e), alkoxy,    alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or    heteroaryl;

an alkyl group, if not stated otherwise, denotes a linear or branchedC₁-C₆-alkyl, preferably a linear or branched chain of one to five carbonatoms, a linear or branched C₂-C₆-alkenyl or a linear or branchedC₂-C₆-alkinyl group, which can optionally be substituted by one or moresubstituents R′;

the C₁-C₆-alkyl, C₂-C₆-alkenyl and C₂-C₆-alkinyl residue may be selectedfrom the group comprising —CH₃, —C₂H₅, —CH═CH₂, —C—CH, —C₃H₇, —CH(CH₃)₂,—CH₂—CH═CH₂, —C(CH₃)═CH₂, —CH═CH—CH₃, —C≡C—CH₃, —CH₂—C—CH, —C₄H₉,—CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅, —C(CH₃)₃, —C₅H₁₁, —C₆H₁₃, —C(R′)₃,—C₂(R′)₅, —CH₂—C(R′)₃, —C₃(R′)₇, —C₂H₄—C(R′)₃, —C₂H₄—CH═CH₂,—CH═CH—C₂H₅, —CH═C(CH₃)₂, —CH₂—CH═CH—CH₃, —CH═CH—CH═CH₂, —C₂H₄—C—CH,—C≡C—C₂H₅, —CH₂—C≡C—CH₃, —C≡C—CH═CH₂, —CH═CH—C—CH, —C≡C—C≡CH,—C₂H₄—CH(CH₃)₂, —CH(CH₃)—C₃H₇, —CH₂—CH(CH₃)—C₂H₅, —CH(CH₃)—CH(CH₃)₂,—C(CH₃)₂—C₂H₅, —CH₂—C(CH₃)₃, —C₃H₆—CH═CH₂, —CH═CH—C₃H₇, —C₂H₄—CH═CH—CH₃,—CH₂—CH═CH—C₂H₅, —CH₂—CH═CH—CH═CH₂, —CH═CH—CH═CH—CH₃, —CH═CH—CH₂—CH═CH₂,—C(CH₃)═CH—CH═CH₂, —CH═C(CH₃)—CH═CH₂, —CH═CH—C(CH₃)═CH₂,—CH₂—CH═C(CH₃)₂, C(CH₃)═C(CH₃)₂, —C₃H₆—C—CH, —C≡C—C₃H₇, —C₂H₄—C≡C—CH₃,—CH₂—C≡C—C₂H₅, —CH₂—C≡C—CH═CH₂, —CH₂—CH═CH—C—CH, —CH₂—C≡C—C≡CH,—C≡C—CH═CH—CH₃, —CH═CH—C≡C—CH₃, —C≡C—C≡C—CH₃, —C≡C—CH₂—CH═CH₂,—CH═CH—CH₂—C—CH, —C≡C—CH₂—C—CH, —C(CH₃)═CH—CH═CH₂, —CH═C(CH₃)—CH═CH₂,—CH═CH—C(CH₃)═CH₂, —C(CH₃)═CH—C—CH, —CH═C(CH₃)—C—CH, —C≡C—C(CH₃)═CH₂,—C₃H₆—CH(CH₃)₂, —C₂H₄—CH(CH₃)—C₂H₅, —CH(CH₃)—C₄H₉, —CH₂—CH(CH₃)—C₃H₇,—CH(CH₃)—CH₂—CH(CH₃)₂, —CH(CH₃)—CH(CH₃)—C₂H₅, —CH₂—CH(CH₃)—CH(CH₃)₂,—CH₂—C(CH₃)₂—C₂H₅, —C(CH₃)₂—C₃H₇, —C(CH₃)₂—CH(CH₃)₂, —C₂H₄—C(CH₃)₃,—CH(CH₃)—C(CH₃)₃, —C₄H₈—CH═CH₂, —CH═CH—C₄H₉, —C₃H₆—CH═CH—CH₃,—CH₂—CH═CH—C₃H₇, —C₂H₄—CH═CH—C₂H₅, —CH₂—C(CH₃)═C(CH₃)₂,—C₂H₄—CH═C(CH₃)₂, —C₄H₈—C—CH, —C≡C—C₄H₉, —C₃H₆—C≡C—CH₃, —CH₂—C≡C—C₃H₇,—C₂H₄—C≡C—C₂H₅;

R′ is independently H, —CO₂R″, —CONHR″, —CR″O, —SO₂NR″,—NR″—CO-haloalkyl, —NO₂, —NR″—SO₂-haloalkyl, —NR″—SO₂-alkyl, —SO₂-alkyl,—NR″—CO-alkyl, —CN, alkyl, cycloalkyl, alkylamino, alkoxy, —OH, —SH,alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl,haloalkyloxy, aryl, or heteroaryl;

R″ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl,or heteroaryl;

a cycloalkyl group denotes a non-aromatic ring system containing threeto eight carbon atoms, preferably four to eight carbon atoms, whereinone or more of the carbon atoms in the ring can be substituted by agroup E, E being O, S, SO, SO₂, N, or NR″, R″ being as defined above;the C₃-C₈-cycloalkyl residue may be selected from the group comprising-cyclo-C₃H₅, -cyclo-C₄H₇, -cyclo-C₅H₉, -cyclo-C₆H₁₁, -cyclo-C₇H₁₃,-cyclo-C₈H₁₅, morpholine-4-yl, piperazinyl, 1-alkylpiperazine-4-yl;

an alkoxy group denotes an O-alkyl group, the alkyl group being asdefined above; the alkoxy group is preferably a methoxy, ethoxy,isopropoxy, t-butoxy or pentoxy group;

an alkylthio group denotes an S-alkyl group, the alkyl group being asdefined above;

an haloalkyl group denotes an alkyl group which is substituted by one tofive halogen atoms, the alkyl group being as defined above; thehaloalkyl group is preferably a —C(R¹⁰)₃, —CR¹⁰(R^(10′))₂,—CR¹⁰(R^(10′))R^(10″), —C₂(R¹⁰)₅, —CH₂—C(R¹⁰)₃, —CH₂—CR¹⁰(R^(10′))₂,—CH₂—CR¹⁰(R^(10′))R^(10″), —C₃(R¹⁰)₇, or —C₂H₄—C(R¹⁰)₃, wherein R¹⁰,R^(10′), R^(10″) represent F, Cl, Br or I, preferably F;

a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being asdefined above;

an haloalkyloxy group denotes an alkoxy group which is substituted byone to five halogen atoms, the alkyl group being as defined above; thehaloalkyloxy group is preferably a —OC(R¹⁰)₃, —OR¹⁰(R^(10′))₂,—OCR¹⁰(R^(10′))R^(10″), —OC₂(R¹⁰)₅, —OCH₂—C(R¹⁰)₃, —OCH₂—CR¹⁰(R¹⁰)₂,—OCH₂—CR¹⁰(R^(10′))R^(10″), —OC₃(R¹⁰)₇ or —OC₂H₄—C(R¹⁰)₃, wherein R¹⁰,R^(10′), R^(10″) represent F, Cl, Br or I, preferably F;

a hydroxyalkylamino group denotes an (HO-alkyl)₂-N— group orHO-alkyl-NH— group, the alkyl group being as defined above;

an alkylamino group denotes an HN-alkyl or N-dialkyl group, the alkylgroup being as defined above;

a halogen group is chlorine, bromine, fluorine or iodine;

an aryl group denotes an aromatic group having five to fifteen carbonatoms, which can optionally be substituted by one or more substituentsR′, where R′ is as defined above; the aryl group is preferably a benzylgroup, a phenyl group, -o-C₆H₄—R′, -m-C₆H₄—R′, -p-C₆H₄—R′, 1-naphthyl,2-naphthyl, 1-anthracenyl or 2-anthracenyl;

a heteroaryl group denotes a 5- or 6-membered heterocyclic group whichcontains at least one heteroatom selected from O, N, and S. Thisheterocyclic group can be fused to another aromatic ring. For example,this group can be selected from a thiadiazole, thiazol-2-yl,thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl,isothiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isooxazol-3-yl,isooxazol-4-yl, isooxazol-5-yl, benzooxazol-2-yl, benzooxazol-4-yl,benzooxazol-5-yl, benzoisooxazol-3-yl, benzoisooxazol-4-yl,benzoisooxazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl,1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,4-thiadiazol-3-yl,1,2,4-thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl,isothiazol-5-yl, benzoisothiazol-3-yl, benzoisothiazol-4-yl,benzoisothiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl,1,2,5-thiadiazol-4-yl, 4-imidazolyl, benzoimidazol-4-yl, 1-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 4-pyranyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl,2,4-dimethoxy-6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl,1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1,2,3-triazol-4-yl,1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl,1,3,5-triazol-6-yl, 2,4-dimethoxy-1,3,5-triazol-6-yl, 1H-tetrazol-2-yl,1H-tetrazol-3-yl, tetrazolyl, acridyl, furazane, indazolyl, phenazinyl,carbazolyl, phenoxazinyl, indolizine, 2-indolyl, 3-indolyl, 4-indolyl,5-indolyl, 6-indolyl, 7-indolyl, 1-isoindolyl, 3-isoindolyl,4-isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-indolinyl,3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl,benzo[b]furanyl, benzofurazane, benzothiofurazane, benzotriazol-1-yl,benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl,benzotriazol-7-yl, benzotriazine, benzo[b]thiophenyl, benzimidazol-2-yl,1H-benzimidazolyl, benzimidazol-4-yl, benzimidazol-5-yl,benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, quinazolinyl,quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl,isoquinolinyl, tetrahydro-thieno[3,4-d]imidazol-2-one,pyrazolo[5,1-c][1,2,4]triazine, tetrahydroisoquinolinyl, purine,phthalazine, pteridine, thiatetraazaindene, thiatriazaindene,isothiazolopyrazine, isothiazolopyrimidine, pyrazolotriazine,pyrazolopyrimidine, imidazopyridazine, imidazo-pyrimidine,imidazopyridine, imidazolotriazine, triazolotriazine, triazolopyridine,triazolo-pyrazine, triazolopyrimidine,2,3-dihydrobenzo[1,4]-dioxin-2-yl, 2,3-dihydrobenzo[1,4]-dioxin-3-yl,2,3-dihydrobenzo[1,4]-dioxin-5-yl, 2,3-dihydrobenzo[1,4]-dioxin-6-yl,2,6-dimethoxypyrimidin-3-yl, 2,6-dimethoxypyrimidin-4-yl,4-[1,2,4]triazolo[4,3-a]pyridin-3-yl, 1-furo[2,3-c]pyridin-4-yl,1-furo[2,3-c]pyridin-5-yl, 1-furo[2,3-c]pyridin-3-yl, andtriazolopyridazine group. This heterocyclic group can be substituted byone or more substituents R′, wherein R′ is as defined above.

The present invention also relates to compounds of the general formula(III) or pharmaceutically acceptable salts thereof with an acid or abase, or pharmaceutically acceptable prodrugs or a stereoisomer thereof,

wherein

-   R¹ is —C(O)R^(7a), —C(O)CHR⁷R⁸, —C(O)NR⁷R⁸, —C(O)OR⁷, —R⁷C(O)R⁸, or    —C(S)R^(7b);-   R² is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl,    hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl,-   or R¹ and R² together with the N-atom or the C-atom to which they    are attached form a 3 to 8 membered saturated or at least partially    unsaturated monocyclic or polycyclic ring system, wherein at least    one or more of the carbon atoms in the ring is a heteroatom selected    from O, N, and S, and the ring can be substituted by one or more R⁹;-   R³ is H, —C(O)NR^(a)R^(b), halogen, alkyl, haloalkyl, aryl,    heteroaryl, OH, SH, NR^(4′)OR^(5′), NH₂, hydroxyalkylamino,    alkylamino, alkoxy, cycloalkyl, heterocycloalkyl, hydroxyalkyl, or    haloalkyloxy;-   R⁴ is H, OH, SH, NH₂, alkoxy, haloalkoxy, halogen, alkyl,    —C(NR⁷)NR^(7′)R⁸, —(CH₂)_(p)aryl, —(CH₂)_(p)NR⁷R⁸, —C(O)NR⁷R⁸,    —N═CR⁷R⁸, —NR⁷C(O)R⁸, cycloalkyl, heterocycloalkyl, haloalkyl,    hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl;-   R⁵ is halogen, alkyl, —C(NR⁷)NR^(7′)R⁸, —(CH₂)_(p)aryl,    —(CH₂)_(p)NR⁷R⁸, —C(O)NR⁷R⁸, —N═CR⁷R⁸, —NR⁷C(O)R⁸, cycloalkyl,    heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino,    alkylamino, heteroaryl, or aryl;-   R^(a) is H, halogen, alkyl, —C(NR⁷)NR^(7′)R⁸, —(CH₂)_(p)aryl,    —(CH₂)_(p)NR⁷R⁸, —C(O)NR⁷R⁸, —N═CR⁷R⁸, —NR⁷C(O)R⁸, cycloalkyl,    heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino,    alkylamino, heteroaryl, or aryl;-   R^(b) independently represents H, —CN, —OH, —SH, —CO₂R^(4′),    —C(O)R^(4′), —SO₂NR^(4′), —NR^(4′)R^(5′), —C(O)NR⁷R⁸, —SO₂-alkyl,    —SO₂R^(4′), SO₃R^(4′), —N═CR^(4′)R^(5′), —NR^(4′)C(O)R^(4″),    —NR⁴—CO-haloalkyl, —NO₂, —NR^(4′)—SO₂-haloalkyl, —NR^(4′)—SO₂-alkyl,    —NR^(4′)—CO-alkyl, —NR^(4′)(CH₂)_(p)heteroaryl, alkyl, cycloalkyl,    alkylamino, alkoxy, alkylthio, halogen, haloalkyl, haloalkyloxy,    —O(CH₂)_(p)[O(CH₂)_(p)]_(q)OCH₃, —C(NR^(4″))NR^(4′)benzimidazolyl,    —C(NR^(4″))NR^(4′)benzthiazolyl, —C(NR^(4″))NR^(4′)benzoxazolyl,    hydroxyalkyl, hydroxy-cycloalkyl, hydroxyalkylamino,    heterocycloalkyl, aryl or heteroaryl;-   R^(4′), R^(4″), R^(5′) independently are H, halogen, alkyl,    —C(NR⁷)NR^(7′)R⁸, —(CH₂)_(p)aryl, haloalkyl, —CH₂)_(p)NR⁷R⁸,    —C(O)NR⁷R⁸, —N═CR⁷R⁸, —NR⁷C(O)R⁸, cycloalkyl, heterocycloalkyl,    hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl;-   R⁷, R^(7′), R⁸ independently are H, halogen, alkyl, cycloalkyl,    heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino,    alkylamino, arylamino heteroaryl, or aryl;-   R^(7a) is cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino,    heteroaryl, or aryl;-   R^(7b) is H, halogen, alkyl, cycloalkyl, heterocycloalkyl,    haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl, or aryl;-   A is CO or SO₂;-   X is NR², O, or S;-   Z is N or CR²;-   R^(2′) is H, alkyl, —C(O)NR⁷, —C(O)R^(b), cycloalkyl,    heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino,    alkylamino, heteroaryl, or aryl;-   p is 1 to 6;-   q is 1 to 6;-   R⁹ independently represents H, —CN, —OH, —SH, alkoxy, alkylthio,    —CO₂R^(4′), —C(O)R^(4a), —C(O)NR⁷R⁸, —SO₂NR^(4′), —NR^(4′)R^(5′),    —SO₂-alkyl, —SO₂R^(4′), SO₃R^(4′), —N═CR^(4′)R^(5′),    —NR^(4′)C(O)R^(4″), —NR^(4′)—CO-haloalkyl, —NO₂,    —NR^(4′)—SO₂-haloalkyl, —NR^(4′)—SO₂-alkyl, —NR^(4′)—CO-alkyl,    —NR^(4′)(CH₂)_(p)heteroaryl, alkyl, hydroxyalkyl, cycloalkyl,    halogen, haloalkyl, alkylamino, —O(CH₂)_(p)[O(CH₂)_(p)]_(q)OCH₃,    —C(NR^(4″))NR^(4′)benzimidazolyl, —C(NR^(4″))NR^(4′)benzthiazolyl,    —C(NR^(4″))NR^(4′)benzoxazolyl, hydroxycycloalkyl,    hydroxyalkylamino, haloalkyloxy, heterocycloalkyl,    —(CH₂)_(p)NR⁷COR⁸, aryl, or heteroaryl;-   R^(4a) is H, C₁-C₆-alkyl, C₂-C₆-alkenyl, cycloalkyl, haloalkyl,    hydroxyalkyl, hydroxyalkylamino, alkylamino, —C(NR⁷)NR^(7′)R⁸,    —(CH₂)_(p)aryl, —(CH₂)_(p)NR⁷R⁸, —C(O)NR⁷R⁸, —N═CR⁷R⁸, —NR⁷C(O)R⁸,    halogen, heteroaryl, or aryl;    wherein

an C₁-C₆-alkyl group, if not stated otherwise, denotes a linear orbranched C₁-C₆-alkyl, preferably a linear or branched chain of one tofive carbon atoms, which can optionally be substituted by one or moresubstituents R′;

an C₂-C₆-alkenyl group, if not stated otherwise, denotes a linear orbranched C₂-C₆-alkenyl, preferably a linear or branched chain of two tosix carbon atoms, which can optionally be substituted by one or moresubstituents R′;

an alkyl group, if not stated otherwise, denotes a linear or branchedC₁-C₆-alkyl, preferably a linear or branched chain of one to six carbonatoms, a linear or branched C₂-C₆-alkenyl or a linear or branchedC₂-C₆-alkynyl group, which can be substituted by one or moresubstituents R′;

R′ is independently H, —CO₂R″, —CONHR″, —CR″O, —SO₂NR″,—NR″—CO-haloalkyl, —NO₂, —NR″—SO₂-haloalkyl, —NR″—SO₂-alkyl, —SO₂-alkyl,—NR″—CO-alkyl, —CN, alkyl, cycloalkyl, alkylamino, alkoxy, —OH, —SH,alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl,haloalkyloxy, aryl, or heteroaryl;

R″ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl,or heteroaryl;

a cycloalkyl group denotes a non-aromatic ring system containing threeto eight carbon atoms, preferably four to eight carbon atoms, whereinone or more of the carbon atoms in the ring can be substituted by agroup R′ being as defined above; the C₃-C₈-cycloalkyl residue may beselected from the group comprising -cyclo-C₃H₅, -cyclo-C₄H₇,-cyclo-C₅H₉, -cyclo-C₆H₁₁, -cyclo-C₇H₁₃, -cyclo-C₈H₁₅;

a heterocycloalkyl group denotes a non-aromatic ring system containingtwo to ten carbon atoms and at least one heteroatom like O, N, or S,wherein one or more of the carbon atoms in the ring can be substitutedby R′ being as defined above; preferred heterocycloalkyl groups aremorpholine-4-yl, piperazinyl, 1-alkylpiperazine-4-yl, piperidinyl,pyrrolidinyl, azepane-1-yl;

an alkoxy group denotes an O-alkyl group, the alkyl group being asdefined above; the alkoxy group is preferably a methoxy, ethoxy,isopropoxy, t-butoxy or pentoxy group;

an alkylthio group denotes an S-alkyl group, the alkyl group being asdefined above;

an haloalkyl group denotes an alkyl group which is substituted by one tofive halogen atoms, the alkyl group being as defined above; thehaloalkyl group is preferably a —C(R¹⁰)₃, —CR¹⁰(R¹⁰)₂,—CR¹⁰(R^(10′))R^(10″), —C₂(R¹⁰)₅, —CH₂C(R¹⁰)₃, —CH₂CR¹⁰(R¹⁰)₂,—CH₂CR¹⁰(R^(10′))R^(10″), —C₃(R¹⁰)₇, or —C₂H₄C(R¹⁰)₃, wherein R¹⁰,R^(10′), R^(10″) represent F, Cl, Br or I, preferably F;

a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being asdefined above;

an haloalkyloxy group denotes an alkoxy group which is substituted byone to five halogen atoms, the alkyl group being as defined above; thehaloalkyloxy group is preferably a —OC(R¹⁰)₃, —OCR¹⁰(R^(10′))₂,—OCR¹⁰(R^(10′))R^(10″), —OC₂(R¹⁰)₅, —OCH₂C(R¹⁰)₃, —OCH₂CR¹⁰(R¹⁰)₂,—OCH₂CR¹⁰(R^(10′))R^(10″), —OC₃(R¹⁰)₇, or —OC₂H₄C(R¹⁰)₃, wherein R¹⁰,R^(10′), R^(10″) represent F, Cl, Br or I, preferably F;

a hydroxyalkylamino group denotes an (HO-alkyl)₂-N— group orHO-alkyl-NH— group, the alkyl group being as defined above;

an alkylamino group denotes an HN-alkyl or N-dialkyl group, the alkylgroup being as defined above;

a halogen group is fluorine, chlorine, bromine, or iodine;

an aryl group denotes an aromatic group having five to fifteen carbonatoms, which can be substituted by one or more substituents R′, where R′is as defined above; the aryl group is preferably a benzyl group, aphenyl group, -o-C₆H₄—R′, -m-C₆H₄—R′, -p-C₆H₄—R′, 1-naphthyl,2-naphthyl, 1-anthracenyl or 2-anthracenyl, R′ being as defined above;

an arylamino group denotes an HN-aryl or N-diaryl group, the aryl groupbeing as defined above;

a heteroaryl group denotes a 5- or 6-membered heterocyclic group whichcontains at least one heteroatom selected from O, N, and S. Thisheterocyclic group can be fused to another aromatic ring. For example,this group can be selected from a thiadiazole, thiazol-2-yl,thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl,isothiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isooxazol-3-yl,isooxazol-4-yl, isooxazol-5-yl, benzooxazol-2-yl, benzooxazol-4-yl,benzooxazol-5-yl, benzoisooxazol-3-yl, benzoisooxazol-4-yl,benzoisooxazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl,1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,4-thiadiazol-3-yl,1,2,4-thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl,isothiazol-5-yl, benzoisothiazol-3-yl, benzoisothiazol-4-yl,benzoisothiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl,1,2,5-thiadiazol-4-yl, 4-imidazolyl, benzoimidazol-4-yl, 1-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 4-pyranyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl,2,4-dimethoxy-6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl,1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1,2,3-triazol-4-yl,1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl,1,3,5-triazol-6-yl, 2,4-dimethoxy-1,3,5-triazol-6-yl, 1H-tetrazol-2-yl,1H-tetrazol-3-yl, tetrazolyl, acridyl, furazane, indazolyl, phenazinyl,carbazolyl, phenoxazinyl, indolizine, 2-indolyl, 3-indolyl, 4-indolyl,5-indolyl, 6-indolyl, 7-indolyl, 1-isoindolyl, 3-isoindolyl,4-isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-indolinyl,3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl,benzo[b]furanyl, benzofurazane, benzothiofurazane, benzotriazol-1-yl,benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl,benzotriazol-7-yl, benzotriazine, benzo[b]thiophenyl, benzimidazol-2-yl,1H-benzimidazolyl, benzimidazol-4-yl, benzimidazol-5-yl,benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, quinazolinyl,quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl,isoquinolinyl, tetrahydro-thieno[3,4-d]imidazol-2-one,pyrazolo[5,1-c][1,2,4]triazine, 2,3-dihydrobenzo[1,4]-dioxin-2-yl,2,3-dihydrobenzo[1,4]-dioxin-3-yl, 2,3-dihydrobenzo[1,4]-dioxin-5-yl,2,3-dihydrobenzo[1,4]-dioxin-6-yl, 2,6-dimethoxypyrimidin-3-yl,2,6-dimethoxypyrimidin-4-yl, tetrahydroisoquinolinyl, purine,phthalazine, pteridine, thiatetraazaindene, thiatriazaindene,isothiazolopyrazine, isothiazolopyrimidine, pyrazolotriazine,pyrazolopyrimidine, imidazopyridazine, imidazo-pyrimidine,imidazopyridine, imidazolotriazine, triazolotriazine, triazolopyridine,triazolopyrazine, triazolopyrimidine,4-[1,2,4]triazolo[4,3-a]pyridin-3-yl, 1-furo[2,3-c]pyridin-4-yl,1-furo[2,3-c]pyridin-5-yl, 1-furo[2,3-c]pyridin-3-yl, andtriazolopyridazine group. This heterocyclic group can be substituted byone or more substituents R′, wherein R′ is as defined above.

A preferred embodiment of the invention, in the compounds of formula(III) are compounds of the general formula (Ih) or pharmaceuticallyacceptable salts thereof with an acid or a base, or pharmaceuticallyacceptable prodrugs or a stereoisomer thereof,

wherein

-   A is NR^(2′), S or O;-   t is 0 to 4;-   r is 0, or 1;-   R^(2a) is independently H, OH, SH, NH₂, alkyl, cycloalkyl,    hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino,    hydroxyalkylamino, halogen, aryl, or heteroaryl;-   R^(3a) is independently H, OH, SH, NH₂, —C(NR⁷)NR^(7′)R⁸,    —(CH₂)_(p)aryl, —(CH₂)_(p)NR⁷R⁸, —C(O)NR⁷R⁸, —N═CR⁷R⁸, —NR⁷C(O)R⁸,    alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy,    alkylamino, hydroxyalkylamino, halogen, aryl, or heteroaryl;-   R^(d) is H, halogen, alkyl, —C(NR⁷)NR^(7′)R⁸, —(CH₂)_(p)aryl,    —(CH₂)_(p)NR⁷R⁸, —C(O)NR⁷R⁸, —N═CR⁷R⁸, —NR⁷C(O)R⁸, cycloalkyl,    haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl    or aryl.-   R¹ is —C(O)R^(7a), —C(O)CHR⁷R⁸, —C(O)NR⁷R⁸, —C(O)OR⁷, —R⁷C(O)R⁸, or    —C(S)R^(7b);-   R² is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl,    hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl,-   or R¹ and R² together with the N-atom or the C-atom to which they    are attached form a 3 to 8 membered saturated or at least partially    unsaturated monocyclic or polycyclic ring system, wherein at least    one or more of the carbon atoms in the ring is a heteroatom selected    from O, N, and S, and the ring can be substituted by one or more R⁹;-   R^(4a) is H, C₁-C₆-alkyl, C₂-C₆-alkenyl, cycloalkyl, haloalkyl,    hydroxyalkyl, hydroxyalkylamino, alkylamino, —C(NR⁷)NR^(7′)R⁸,    —(CH₂)_(p)aryl, —(CH₂)_(p)NR⁷R⁸, —C(O)NR⁷R⁸, —N═CR⁷R⁸, —NR⁷C(O)R⁸,    halogen, heteroaryl, or aryl;-   R³ is H, —C(O)NR^(a)R^(b), halogen, alkyl, haloalkyl, aryl,    heteroaryl, OH, SH, NR^(4′)OR^(5′), NH₂, hydroxyalkylamino,    alkylamino, alkoxy, cycloalkyl, heterocycloalkyl, hydroxyalkyl, or    haloalkyloxy;-   R^(a) is H, halogen, alkyl, —C(NR⁷)NR^(7′)R⁸, —(CH₂)_(p)aryl,    —(CH₂)_(p)NR⁷R⁸, —C(O)NR⁷R⁸, —N═CR⁷R⁸, —NR⁷C(O)R⁸, cycloalkyl,    heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino,    alkylamino, heteroaryl, or aryl;

R^(b) independently represents H, —CN, —OH, —SH, —CO₂R^(4′),—C(O)R^(4′), —SO₂NR^(4′), —NR^(4′)R^(5′), —C(O)NR⁷R⁸, —SO₂-alkyl,—SO₂R^(4′), SO₃R^(4′), —N═CR^(4′)R^(5′), —NR^(4′)C(O)R^(4″),—NR^(4′)—CO-haloalkyl, —NO₂, —NR^(4′)—SO₂-haloalkyl, —NR^(4′)—SO₂-alkyl,—NR^(4′)—CO-alkyl, —NR^(4′)(CH₂)_(p)heteroaryl, alkyl, cycloalkyl,alkylamino, alkoxy, alkylthio, halogen, haloalkyl, haloalkyloxy,—O(CH₂)_(p)[O(CH₂)_(p)]_(q)OCH₃, —C(NR^(4″))NR^(4′)benzimidazolyl,—C(NR^(4″))NR^(4′)benzthiazolyl, —C(NR^(4″))NR^(4′)benzoxazolyl,hydroxyalkyl, hydroxy-cycloalkyl, hydroxyalkylamino, heterocycloalkyl,aryl or heteroaryl;

-   R^(4′), R^(4″), R^(5′) independently are H, halogen, alkyl,    —C(NR⁷)NR^(7′)R⁸, —(CH₂)_(p)aryl, haloalkyl, —CH₂)_(p)NR⁷R⁸,    —C(O)NR⁷R⁸, —N═CR⁷R⁸, —NR⁷C(O)R⁸, cycloalkyl, heterocycloalkyl,    hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl;-   R⁷, R^(7′), R⁸ independently are H, halogen, alkyl, cycloalkyl,    heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino,    alkylamino, arylamino heteroaryl, or aryl;-   R^(7a) is cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino,    heteroaryl, or aryl;-   R^(7b) is H, halogen, alkyl, cycloalkyl, heterocycloalkyl,    haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl, or aryl;-   X is NR^(2′), O, or S;-   Z is N or CR^(2′);-   R^(2′) is H, alkyl, —C(O)NR⁷, —C(O)R^(b), cycloalkyl,    heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino,    alkylamino, heteroaryl, or aryl;-   p is 1 to 6;-   q is 1 to 6;-   R⁹ independently represents H, —CN, —OH, —SH, alkoxy, alkylthio,    —CO₂R⁴, —C(O)R^(4a), —C(O)NR⁷R⁸, —SO₂NR^(4′), —NR^(4′)R^(5′),    —SO₂-alkyl, —SO₂R^(4′), SO₃R^(4′), —N═CR^(4′)R^(5′),    —NR^(4′)C(O)R^(4″), —NR^(4′)—CO-haloalkyl, —NO₂,    —NR^(4′)—SO₂-haloalkyl, —NR^(4′)—SO₂-alkyl, —NR^(4′)—CO-alkyl,    —NR^(4′)(CH₂)_(p)heteroaryl, alkyl, hydroxyalkyl, cycloalkyl,    halogen, haloalkyl, alkylamino, —O(CH₂)_(p)[O(CH₂)_(p)]_(q)OCH₃,    —C(NR^(4″))NR^(4′)benzimidazolyl, —C(NR^(4″))NR^(4′)benzthiazolyl,    —C(NR^(4″))NR^(4′)benzoxazolyl, hydroxycycloalkyl,    hydroxyalkylamino, haloalkyloxy, heterocycloalkyl,    —(CH₂)_(p)NR⁷COR⁸, aryl, or heteroaryl;    wherein

an C₁-C₆-alkyl group, if not stated otherwise, denotes a linear orbranched C₁-C₆-alkyl, preferably a linear or branched chain of one tofive carbon atoms, which can optionally be substituted by one or moresubstituents R′;

an C₂-C₆-alkenyl group, if not stated otherwise, denotes a linear orbranched C₂-C₆-alkenyl, preferably a linear or branched chain of two tosix carbon atoms, which can optionally be substituted by one or moresubstituents R′;

an alkyl group, if not stated otherwise, denotes a linear or branchedC₁-C₆-alkyl, preferably a linear or branched chain of one to six carbonatoms, a linear or branched C₂-C₆-alkenyl or a linear or branchedC₂-C₆-alkynyl group, which can be substituted by one or moresubstituents R′;

R′ is independently H, —CO₂R″, —CONHR″, —CR″O, —SO₂NR″,—NR″—CO-haloalkyl, —NO₂, —NR″—SO₂-haloalkyl, —NR″—SO₂-alkyl, —SO₂-alkyl,—NR″—CO-alkyl, —CN, alkyl, cycloalkyl, alkylamino, alkoxy, —OH, —SH,alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl,haloalkyloxy, aryl, or heteroaryl;

R″ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl,or heteroaryl;

a cycloalkyl group denotes a non-aromatic ring system containing threeto eight carbon atoms, preferably four to eight carbon atoms, whereinone or more of the carbon atoms in the ring can be substituted by agroup R′ being as defined above; the C₃-C₈-cycloalkyl residue may beselected from the group comprising -cyclo-C₃H₅, -cyclo-C₄H₇,-cyclo-C₅H₉, -cyclo-C₆H₁₁, -cyclo-C₇H₁₃, -cyclo-C₈H₁₅;

a heterocycloalkyl group denotes a non-aromatic ring system containingtwo to ten carbon atoms and at least one heteroatom selected from O, N,and S, wherein one or more of the carbon atoms in the ring can besubstituted by R′ being as defined above; preferred heterocycloalkylgroups are morpholine-4-yl, piperazinyl, 1-alkylpiperazine-4-yl,piperidinyl, pyrrolidinyl, azepane-1-yl;

an alkoxy group denotes an O-alkyl group, the alkyl group being asdefined above; the alkoxy group is preferably a methoxy, ethoxy,isopropoxy, t-butoxy or pentoxy group;

an alkylthio group denotes an S-alkyl group, the alkyl group being asdefined above;

an haloalkyl group denotes an alkyl group which is substituted by one tofive halogen atoms, the alkyl group being as defined above; thehaloalkyl group is preferably a —C(R¹⁰)₃, —CR¹⁰(R¹⁰)₂,—CR¹⁰(R^(10′))R^(10″), —C₂(R¹⁰)₅, —CH₂C(R¹⁰)₃, —CH₂CR¹⁰(R^(10′))₂,—CH₂CR¹⁰(R^(10′))R^(10″), —C₃(R¹⁰)₇, or —C₂H₄C(R¹⁰)₃, wherein R¹⁰,R^(10′), R^(10″) represent F, Cl, Br or I, preferably F;

a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being asdefined above;

an haloalkyloxy group denotes an alkoxy group which is substituted byone to five halogen atoms, the alkyl group being as defined above; thehaloalkyloxy group is preferably a —OC(R¹⁰)₃, —OCR¹⁰(R^(10′))₂,—OCR¹⁰(R^(10′))R^(10″), —OC₂(R¹⁰)₅, —OCH₂C(R¹⁰)₃, —OCH₂CR¹⁰(R¹⁰)₂,—OCH₂CR¹⁰(R^(10′))R^(10″), —OC₃(R¹⁰)₇, or —OC₂H₄C(R¹⁰)₃, wherein R¹⁰,R^(10′), R^(10″) represent F, Cl, Br or I, preferably F;

a hydroxyalkylamino group denotes an (HO-alkyl)₂-N— group orHO-alkyl-NH— group, the alkyl group being as defined above;

an alkylamino group denotes an HN-alkyl or N-dialkyl group, the alkylgroup being as defined above;

a halogen group is fluorine, chlorine, bromine, or iodine;

an aryl group denotes an aromatic group having five to fifteen carbonatoms, which can be substituted by one or more substituents R′, where R′is as defined above; the aryl group is preferably a benzyl group, aphenyl group, -o-C₆H₄—R′, -m-C₆H₄—R′, -p-C₆H₄—R′, 1-naphthyl,2-naphthyl, 1-anthracenyl or 2-anthracenyl, R′ being as defined above;

an arylamino group denotes an HN-aryl or N-diaryl group, the aryl groupbeing as defined above;

a heteroaryl group denotes a 5- or 6-membered heterocyclic group whichcontains at least one heteroatom selected from O, N, and S. Thisheterocyclic group can be fused to another aromatic ring. For example,this group can be selected from a thiadiazole, thiazol-2-yl,thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl,isothiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isooxazol-3-yl,isooxazol-4-yl, isooxazol-5-yl, benzooxazol-2-yl, benzooxazol-4-yl,benzooxazol-5-yl, benzoisooxazol-3-yl, benzoisooxazol-4-yl,benzoisooxazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl,1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,4-thiadiazol-3-yl,1,2,4-thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl,isothiazol-5-yl, benzoisothiazol-3-yl, benzoisothiazol-4-yl,benzoisothiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl,1,2,5-thiadiazol-4-yl, 4-imidazolyl, benzoimidazol-4-yl, 1-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 4-pyranyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl,2,4-dimethoxy-6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl,1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1,2,3-triazol-4-yl,1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl,1,3,5-triazol-6-yl, 2,4-dimethoxy-1,3,5-triazol-6-yl, 1H-tetrazol-2-yl,1H-tetrazol-3-yl, tetrazolyl, acridyl, furazane, indazolyl, phenazinyl,carbazolyl, phenoxazinyl, indolizine, 2-indolyl, 3-indolyl, 4-indolyl,5-indolyl, 6-indolyl, 7-indolyl, 1-isoindolyl, 3-isoindolyl,4-isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-indolinyl,3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl,benzo[b]furanyl, benzofurazane, benzothiofurazane, benzotriazol-1-yl,benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl,benzotriazol-7-yl, benzotriazine, benzo[b]thiophenyl, benzimidazol-2-yl,1H-benzimidazolyl, benzimidazol-4-yl, benzimidazol-5-yl,benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, quinazolinyl,quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl,isoquinolinyl, tetrahydro-thieno[3,4-d]imidazol-2-one,pyrazolo[5,1-c][1,2,4]triazine, 2,3-dihydrobenzo[1,4]-dioxin-2-yl,2,3-dihydrobenzo[1,4]-dioxin-3-yl, 2,3-dihydrobenzo[1,4]-dioxin-5-yl,2,3-dihydrobenzo[1,4]-dioxin-6-yl, 2,6-dimethoxypyrimidin-3-yl,2,6-dimethoxypyrimidin-4-yl, tetrahydroisoquinolinyl, purine,phthalazine, pteridine, thiatetraazaindene, thiatriazaindene,isothiazolopyrazine, isothiazolopyrimidine, pyrazolotriazine,pyrazolopyrimidine, imidazopyridazine, imidazo-pyrimidine,imidazopyridine, imidazolotriazine, triazolotriazine, triazolopyridine,triazolopyrazine, triazolopyrimidine,4-[1,2,4]triazolo[4,3-a]pyridin-3-yl, 1-furo[2,3-c]pyridin-4-yl,1-furo[2,3-c]pyridin-5-yl, 1-furo[2,3-c]pyridin-3-yl, andtriazolopyridazine group. This heterocyclic group can be substituted byone or more substituents R′, wherein R′ is as defined above.

The present invention relates also to compounds of the general formula(II) or pharmaceutically acceptable salts thereof with an acid or abase, or pharmaceutically acceptable prodrugs, or a stereoisomerthereof,

wherein

-   R¹ is —C(O)R⁷, —C(O)CHR⁷R⁸, —C(O)NR⁷R⁸, —C(O)OR⁷, —R⁷C(O)R⁸,    —C(S)R⁷;-   R² is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl,    hydroxyalkyl, alkylamino, hydroxyalkylamino, heteroaryl,-   or R¹ and R² together with the N-atom or the C-atom to which they    are attached form a 3 to 8 membered saturated or at least partially    unsaturated monocyclic or polycyclic ring system, wherein at least    one or more of the carbon atoms in the ring is a heteroatom selected    from O, N, and S, and the ring can be substituted by one or more R⁹;-   R³ is H, —C(O)NR^(a)R^(b), halogen, alkyl, haloalkyl, aryl,    heteroaryl, OH, SH, NR^(4′)OR^(5′), NH₂, hydroxyalkylamino,    alkylamino, alkoxy, cycloalkyl, heterocycloalkyl, hydroxyalkyl, or    haloalkyloxy;-   R^(a) is H, halogen, alkyl, —C(NR⁷)NR^(7′)R⁸, —(CH₂)_(p)aryl,    —(CH₂)_(p)NR⁷R⁸, —C(O)NR⁷R⁸, —N═CR⁷R⁸, —NR⁷C(O)R⁸, cycloalkyl,    heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino,    alkylamino, heteroaryl, or aryl;-   R^(b) independently represents H, —CN, —OH, —SH, —CO₂R^(4′),    —C(O)R^(4′), —SO₂NR^(4′), —NR^(4′)R^(5′), —C(O)NR⁷R⁸, —SO₂-alkyl,    —SO₂R^(4′), SO₃R^(4′), —N═CR^(4′)R^(5′), —NR^(4′)C(O)R^(4″),    —NR^(4′)—CO-haloalkyl, —NO₂, —NR^(4′)—SO₂-haloalkyl,    —NR^(4′)—SO₂-alkyl, —NR^(4′)—CO-alkyl, —NR^(4′)(CH₂)_(p)heterocycle,    alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, halogen,    haloalkyl, haloalkyloxy, —O(CH₂)_(p)[O(CH₂)_(p)]_(q)OCH₃,    —C(NR^(4″))NR^(4′)benzimidazolyl, —C(NR^(4″))NR^(4′)benzthiazolyl,    —C(NR^(4″))NR^(4′)benzoxazolyl, hydroxyalkyl, hydroxy-alkylamino,    aryl, heterocycloalkyl, or heteroaryl;-   R⁶ is halogen, —C(O)R⁷, —C(O)CHR⁷R⁸, —C(O)NR⁷R⁸, —C(O)OR⁷,    —R⁷C(O)R⁸, —C(S)R⁷, —C(NR⁷)NR^(7′)R⁸, —(CH₂)_(p)aryl,    —(CH₂)_(p)NR⁷R⁸, —C(O)NR⁷R⁸, —N═CR⁷R⁸, —NR⁷C(O)R⁷, alkyl,    cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl,    hydroxyalkylamino, alkylamino, heteroaryl, or aryl;-   R⁷, R^(7′), R⁸ independently are H, halogen, alkyl, cycloalkyl,    heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino,    alkylamino, —NHaryl, heteroaryl, or aryl;-   A is CO or SO₂;-   X is NR^(2′), O, or S;-   Y is N, CR^(2′) or if Y is O then R⁶ is absent;-   Z is N or CR^(2′); if Z is CH then X is or NR^(2′)-   R^(2′) is H, alkyl, —C(O)NR², —C(O)R^(b), cycloalkyl,    heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino,    alkylamino, heteroaryl, or aryl;-   n is 0 to 2;-   p is 1 to 6;-   q is 1 to 6;-   R⁹ independently represents H, —CN, —OH, —SH, —CO₂R⁴, —C(O)R^(4a),    —C(O)NR⁷R⁸, —SO₂NR^(4′), —NR^(4′)R^(5′), —SO₂-alkyl, —SO₂R^(4′),    SO₃R^(4′), —N═CR^(4′)R^(5′), —NR^(4′)C(O)R^(4″),    —NR^(4′)—CO-haloalkyl, —NO₂, —NR^(4′)—SO₂-haloalkyl,    —NR^(4′)—SO₂-alkyl, —NR^(4′)—CO-alkyl, —NR^(4′)(CH₂)_(p)heteroaryl,    alkyl, cycloalkyl, heterocycloalkyl, alkylamino, alkoxy, alkylthio,    halogen, haloalkyl, haloalkyloxy, hydroxyalkylamino, hydroxyalkyl,    hydroxycycloalkyl, aryl, —O(CH₂)_(p)[O(CH₂)_(p)]_(q)OCH₃,    —C(NR^(4″))NR^(4′)benzimidazolyl, —C(NR^(4″))NR^(4′)benzthiazolyl,    —C(NR^(4″))NR^(4′)benzoxazolyl, —(CH₂)_(p)NR⁷COR⁸, or heteroaryl;-   R⁴, R^(4″), R⁵ independently are H, halogen, alkyl,    —C(NR⁷)NR^(7′)R⁸, —(CH₂)_(p)aryl, —(CH₂)_(p)NR⁷R⁸, —C(O)NR⁷R⁸,    —N═CR⁷R⁸, —NR⁷C(O)R⁸, cycloalkyl, heterocycloalkyl, haloalkyl,    hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl;-   R^(4a) is H, C₁-C₆-alkyl, C₂-C₆-alkenyl, cycloalkyl, haloalkyl,    hydroxyalkyl, hydroxyalkylamino, alkylamino, —C(NR⁷)NR^(7′)R⁸,    —(CH₂)_(p)aryl, —CH₂)_(p)NR⁷R⁸, —C(O)NR⁷R⁸, —N═CR⁷R⁸, —NR⁷C(O)R⁸,    halogen, heteroaryl, or aryl    wherein

an C₁-C₆-alkyl group, if not stated otherwise, denotes a linear orbranched C₁-C₆-alkyl, preferably a linear or branched chain of one tofive carbon atoms, which can optionally be substituted by one or moresubstituents R′;

an C₂-C₆-alkenyl group, if not stated otherwise, denotes a linear orbranched C₂-C₆-alkenyl, preferably a linear or branched chain of two tosix carbon atoms, which can optionally be substituted by one or moresubstituents R′;

an alkyl group, if not stated otherwise, denotes a linear or branchedC₁-C₆-alkyl, preferably a linear or branched chain of one to six carbonatoms, a linear or branched C₂-C₆-alkenyl or a linear or branchedC₂-C₆-alkynyl group, which can be substituted by one or moresubstituents R′;

R′ is independently H, —CO₂R″, —CONHR″, —CR″O, —SO₂NR″,—NR″—CO-haloalkyl, —NO₂, —NR″—SO₂-haloalkyl, —NR″—SO₂-alkyl, —SO₂-alkyl,—NR″—CO-alkyl, —CN, alkyl, cycloalkyl, alkylamino, alkoxy, —OH, —SH,alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl,haloalkyloxy, aryl, or heteroaryl;

R″ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl,or heteroaryl;

a heterocycle denotes a heterocycloalkyl group or a heteroaryl group;

a cycloalkyl group denotes a non-aromatic ring system containing threeto eight carbon atoms, preferably four to eight carbon atoms, whereinone or more of the carbon atoms in the ring can be substituted by agroup R′ being as defined above; the C₃-C₈-cycloalkyl residue may beselected from the group comprising -cyclo-C₃H₅, -cyclo-C₄H₇,-cyclo-C₅H₉, -cyclo-C₆H₁₁, -cyclo-C₇H₁₃, -cyclo-C₈H₁₅;

a heterocycloalkyl group denotes a non-aromatic ring system containingtwo to ten carbon atoms and at least one heteroatom selected from O, N,and S, wherein one or more of the carbon atoms in the ring can besubstituted by R′ being as defined above; preferred heterocycloalkylgroups are morpholine-4-yl, piperazinyl, 1-alkylpiperazine-4-yl,piperidinyl, pyrrolidinyl, azocane-1-yl;

an alkoxy group denotes an O-alkyl group, the alkyl group being asdefined above; the alkoxy group is preferably a methoxy, ethoxy,isopropoxy, t-butoxy or pentoxy group;

an alkylthio group denotes an S-alkyl group, the alkyl group being asdefined above;

an haloalkyl group denotes an alkyl group which is substituted by one tofive halogen atoms, the alkyl group being as defined above; thehaloalkyl group is preferably a —C(R¹⁰)₃, —CR¹⁰(R¹⁰)₂,—CR¹⁰(R^(10′))R^(10″), —C₂(R¹⁰)₅, —CH₂C(R¹⁰)₃, —CH₂CR¹⁰(R^(10′))₂,—CH₂CR¹⁰(R^(10′))R^(10″), —C₃(R¹⁰)₇, or —C₂H₄C(R¹⁰)₃, wherein R¹⁰,R^(10′), R^(10″) represent F, Cl, Br or I, preferably F;

a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being asdefined above;

an haloalkyloxy group denotes an alkoxy group which is substituted byone to five halogen atoms, the alkyl group being as defined above; thehaloalkyloxy group is preferably a —OC(R¹⁰)₃, —OCR¹⁰(R^(10′))₂,—OCR¹⁰(R^(10′))R^(10″), —OC₂(R¹⁰)₅, —OCH₂C(R¹⁰)₃, —OCH₂CR¹⁰(R^(10′))₂,—OCH₂CR¹⁰(R^(10′))R^(10″), —OC₃(R¹⁰)₇, or —OC₂H₄C(R¹⁰)₃, wherein R¹⁰,R^(10′), R^(10″) represent F, Cl, Br or I, preferably F;

a hydroxyalkylamino group denotes an (HO-alkyl)₂-N— group orHO-alkyl-NH— group, the alkyl group being as defined above;

an alkylamino group denotes an HN-alkyl or N-dialkyl group, the alkylgroup being as defined above;

a halogen group is fluorine, chlorine, bromine, or iodine;

an aryl group denotes an aromatic group having five to fifteen carbonatoms, which can be substituted by one or more substituents R′, where R′is as defined above; the aryl group is preferably a benzyl group, aphenyl group, -o-C₆H₄—R′, -m-C₆H₄—R′, -p-C₆H₄—R′, 1-naphthyl,2-naphthyl, 1-anthracenyl or 2-anthracenyl, R′ being as defined above;

a heteroaryl group denotes a 5- or 6-membered heterocyclic group whichcontains at least one heteroatom selected from O, N, and S. Thisheterocyclic group can be fused to another aromatic ring. For example,this group can be selected from a thiadiazole, thiazol-2-yl,thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl,isothiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isooxazol-3-yl,isooxazol-4-yl, isooxazol-5-yl, benzooxazol-2-yl, benzooxazol-4-yl,benzooxazol-5-yl, benzoisooxazol-3-yl, benzoisooxazol-4-yl,benzoisooxazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl,1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,4-thiadiazol-3-yl,1,2,4-thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl,isothiazol-5-yl, benzoisothiazol-3-yl, benzoisothiazol-4-yl,benzoisothiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl,1,2,5-thiadiazol-4-yl, 4-imidazolyl, benzoimidazol-4-yl, 1-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 4-pyranyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl,2,4-dimethoxy-6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl,1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1,2,3-triazol-4-yl,1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl,1,3,5-triazol-6-yl, 2,4-dimethoxy-1,3,5-triazol-6-yl, 1H-tetrazol-2-yl,1H-tetrazol-3-yl, tetrazolyl, acridyl, furazane, indazolyl, phenazinyl,carbazolyl, phenoxazinyl, indolizine, 2-indolyl, 3-indolyl, 4-indolyl,5-indolyl, 6-indolyl, 7-indolyl, 1-isoindolyl, 3-isoindolyl,4-isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-indolinyl,3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl,benzo[b]furanyl, benzofurazane, benzothiofurazane, benzotriazol-1-yl,benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl,benzotriazol-7-yl, benzotriazine, benzo[b]thiophenyl, benzimidazol-2-yl,1H-benzimidazolyl, benzimidazol-4-yl, benzimidazol-5-yl,benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, quinazolinyl,quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl,isoquinolinyl, tetrahydro-thieno[3,4-d]imidazol-2-one,pyrazolo[5,1-c][1,2,4]triazine, 2,3-dihydrobenzo[1,4]-dioxin-2-yl,2,3-dihydrobenzo[1,4]-dioxin-3-yl, 2,3-dihydrobenzo[1,4]-dioxin-5-yl,2,3-dihydrobenzo[1,4]-dioxin-6-yl, 2,6-dimethoxypyrimidin-3-yl,2,6-dimethoxypyrimidin-4-yl, tetrahydroisoquinolinyl, purine,phthalazine, pteridine, thiatetraazaindene, thiatriazaindene,isothiazolopyrazine, isothiazolopyrimidine, pyrazolotriazine,pyrazolopyrimidine, imidazopyridazine, imidazopyrimidine,imidazopyridine, imidazolotriazine, triazolotriazine, triazolopyridine,triazolopyrazine, triazolopyrimidine,4-[1,2,4]triazolo[4,3-a]pyridin-3-yl, 1-furo[2,3-c]pyridin-4-yl,1-furo[2,3-c]pyridin-5-yl, 1-furo[2,3-c]pyridin-3-yl, andtriazolopyridazine group. This heterocyclic group can be substituted byone or more substituents R′, wherein R′ is as defined above.

In a preferred embodiment of the invention, in the compounds of formula(Ia), Z is S, Y is CO, X is CO, R is H, R^(c) is H, and R¹ is aryl,benzyl, or heteroaryl, R² is

and R⁵ is optionally substituted aryl, benzyl or heteroaryl.

In a preferred embodiment of the invention, in the compounds of formula(Ia), Z is 0, Y is CO, X is CO, R is H, R^(c) is H, and R¹ is aryl,benzyl, or heteroaryl, R² is

and R⁵ is optionally substituted aryl, benzyl or heteroaryl.

In a preferred embodiment of the invention, in the compounds of formula(Ib), Z is S, Y is CO, X forms a piperidine ring together with R¹ andR⁴, R^(a) and R^(b) is H, R^(c) is H or methyl, R² is

and R⁵ is optionally substituted aryl, benzyl or heteroaryl.

In a preferred embodiment of the invention, in the compounds of formula(Ib), Z is O, Y is CO, X forms a piperidine ring together with R¹ andR⁴, R^(a) and R^(b) is H, R^(c) is H or methyl, R² is

and R⁵ is optionally substituted aryl, benzyl or heteroaryl.

In another preferred embodiment, in the compounds of formula (Ic), r is1, Y is CO, Z is O, t is 0, s is 1, X is CO, R^(e) is H, methyl, ethyl,methoxy, alkylamino, morpholino, N-methylpiperazine, CF₃, or OCF, R² is

and R⁵ is optionally substituted aryl, benzyl or heteroaryl.

In another preferred embodiment, in the compounds of formula (Ic), r is1, Y is CO, Z is S, t is 0, s is 0, R^(c) is H, methyl, ethyl, methoxy,alkylamino, morpholino, N-methylpiperazine, CF₃, or OCF, R² is

and R⁵ is optionally substituted aryl, benzyl or heteroaryl.

In another preferred embodiment, in the compounds of formula (Ic), r is1, Y is CO, Z is S, t is 0, s is 1, X is CO, R^(c) is H, methyl, ethyl,methoxy, alkylamino, morpholino, N-methylpiperazine, CF₃, or OCF, R² is

and R⁵ is optionally substituted aryl, benzyl or heteroaryl.

In another preferred embodiment, in the compounds of formula (Ic), r is1, Y is CO, Z is O, t is 0, s is 0, R^(c) is H, methyl, ethyl, methoxy,alkylamino, morpholino, N-methylpiperazine, CF₃, or OCF, R² is

and R⁵ is optionally substituted aryl, benzyl or heteroaryl.

A preferred embodiment of the invention, in the compounds of formula(III), are compounds of the formula (IIIa),

wherein

R³ is H, methyl, methoxy, CF₃, or OCF₃; R⁴, R⁵, R^(7a) are defined asabove; X is NR^(2′), O or S; and

Z is as defined as above.

Another preferred embodiment of the invention, in the compounds offormula (III), are compounds of the formula (IIIa), withR^(7a)=—NH-aryl.

Another preferred embodiment of the invention, in the compounds offormula (III), are compounds of the formula (IIIb),

wherein

R³ is H, methyl, methoxy, CF₃, or OCF₃; R⁵ is defined as above; X isNR^(2′), O or S; if Z is N then X is NR^(2′), O or S, or if Z isCR^(2′), X is O; Y′ is O or NR^(2′), R^(2′) is as defined above.

Another preferred embodiment of the invention, in the compounds offormula (III), are compounds of the formula (IIIc),

wherein

-   R¹¹, R¹² independently represent H, —CN, —OH, —SH, —CO₂R^(4′),    —C(O)R⁴, —SO₂NR⁴, —NR^(4′)R^(5′), —SO₂-alkyl, —SO₂R^(4′), SO₃R^(4′),    —N═CR^(4′)R^(5′), —NR^(4′)C(O)R⁴, —NR⁴—CO-haloalkyl, —NO₂,    —NR^(4′)—SO₂-haloalkyl, —NR^(4′)—SO₂-alkyl, —NR^(4′)—CO-alkyl,    —NR^(4′) (CH₂)_(p)heteroaryl, alkyl, cycloalkyl, alkylamino, alkoxy,    alkylthio, —O(CH₂)_(p)[O(CH₂)_(p)]_(q)OCH₃,    —C(NR^(4″))NR^(4′)benzimidazolyl, —C(NR^(4″))NR^(4′)benzthiazolyl,    —C(NR^(4″))NR^(4′)benzoxazolyl hydroxyalkyl, hydroxycycloalkyl,    hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl    or a heterocycle; and R^(4′), R^(4″), R^(5′) are defined as above;-   R³ is H, methyl, methoxy, CF₃, or OCF₃; X is NR^(2′), O or S, R⁴ is    defined as above,-   R⁷ and R^(7′) are defined as above,-   R^(11′), R^(12′) independently represents H, —CN, —OH, —SH,    —CO₂R^(4′), —C(O)R^(4′), —SO₂NR^(4′), —NR^(4′)R^(5′), —SO₂-alkyl,    —SO₂R^(4′), SO₃R^(4′), —N═CR^(4′)R^(5′), —NR^(4′)C(O)R⁴,    —NR⁴—CO-haloalkyl, —NO₂, —NR^(4′)—SO₂-haloalkyl, —NR^(4′)—SO₂-alkyl,    —NR^(4′)—CO-alkyl, —NR^(4′) (CH₂)_(p)heteroaryl, alkyl, cycloalkyl,    alkylamino, alkoxy, alkylthio, —O(CH₂)_(p)[O(CH₂)_(p)]_(q)OCH₃,    —C(NR^(4″))NR^(4′)benzimidazolyl, —C(NR^(4″))NR^(4′)benzthiazolyl,    —C(NR^(4″))NR^(4′)benzoxazolyl hydroxyalkyl, hydroxycycloalkyl,    hydroxyalkyl-amino, halogen, haloalkyl, haloalkyloxy, aryl,    arylalkyl or a heterocycle; and R^(4′), R^(4″), R^(5′) are defined    as above.

A more preferred embodiment of the invention, in the compounds offormula (III), are compounds of the formula (IIId),

wherein

R³ is H, methyl, methoxy, CF₃, or OCF₃; X is NR^(2′), O or S, R⁴ isdefined as above, R⁷ and R^(7′) are defined as above, Y″ and R^(11′),R^(12′) are defined as above under formula (IIIc), Y′ is O or NR^(2′)and R^(2′) is as defined above.

Another more preferred embodiment of the invention, in the compounds offormula (III), are compounds of the formula (IIIe),

wherein

R³, R⁴ and R⁵ are defined as above, X is O or S, R¹¹ and R¹² are definedas above under formula (IIIc), and if Z is N, X is NR^(2′), O or S, if Zis CH, X is O.

Another more preferred embodiment of the invention, in the compounds offormula (III), are compounds of the formula (IIIf),

wherein

Z is N or CH, and R³ is H, methyl, methoxy, CF₃, or OCF₃; X is NR^(2′),O or S, R⁴ is defined as above, R⁷ and R^(7′) are defined as above,R^(2′) is as defined above; Y″ and R¹¹, R^(11′), R¹², R^(12′) aredefined as above under formula (IIIc).

A preferred embodiment of the invention, are compounds of the formula(Iha),

wherein

R¹ is COR^(7a); R² and R^(3a) are H; A is NH; R⁷ is as defined above; Zis N; X is NR^(2′), O or S; R³ is H, methyl, ethyl, methoxy, amine,alkylamine, morpholino, N-methylpiperazine, CF₃, or OCF₃; t is 0; r is1; and R^(2a) is optionally substituted aryl, benzyl or heteroaryl.

Another preferred embodiment of the invention, in the compounds offormula (Ih), are compounds of the formula (Iha), with R^(7a) isoptionally substituted aryl, benzyl or heteroaryl.

Another preferred embodiment of the invention, in the compounds offormula (Ih), are compounds of the formula (Ihb),

wherein

R^(3a) is H; A is NH; X is NR^(2′), O or S; Y′ is O or NR^(2′); R^(2′)isas defined above; R³ is H, methyl, ethyl, methoxy, amine, alkylamine,morpholino, N-methylpiperazine, CF₃, or OCF₃; t is 0; r is 1; and R^(2a)is optionally substituted aryl, benzyl or heteroaryl.

Another more preferred embodiment of the invention, in the compounds offormula (Ih), are compounds of the formula (Ihe),

wherein

-   R^(3a) is H;-   A is NH;-   X is NR^(2′), O or S;-   R¹¹ and R¹² independently represent H, —CN, —OH, —SH, —CO₂R^(4′),    —C(O)R⁴, —SO₂NR⁴, —NR⁴, R⁵, —SO₂-alkyl, —SO₂R^(4′), SO₃R^(4′),    —N═CR^(4′)R^(5′), —NR^(4′)C(O)R⁴, —NR⁴—CO-haloalkyl, —NO₂,    —NR^(4′)—SO₂-haloalkyl, —NR^(4′)—SO₂-alkyl, —NR^(4′)—CO-alkyl,    —NR^(4′)(CH₂)_(p)heteroaryl, alkyl, cycloalkyl, alkylamino, alkoxy,    alkylthio, —O(CH₂)_(p)[O(CH₂)_(p)]_(q)OCH₃,    —C(NR^(4″))NR^(4′)benzimidazolyl, —C(NR^(4″))NR^(4′)benzthiazolyl,    —C(NR^(4″))NR^(4′)benzoxazolyl hydroxyalkyl, hydroxycycloalkyl,    hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl    or a heterocycle; and R^(4′), R^(4″), R^(5′) are defined as above;-   R^(2′) is as defined above;-   R³ is H, methyl, ethyl, methoxy, amine, alkylamine, morpholino,    N-methylpiperazine, CF₃, or OCF₃; t is 0; r is 1; and R², is    optionally substituted aryl, benzyl or heteroaryl.

A preferred embodiment of the invention, in the compounds of formula(II), are compounds of the formula (IIa),

wherein

R¹ and R² are defined as above, Z is defined as above; X is O or S; R³is H, methyl, methoxy, CF₃, or OCF₃; R¹¹ and R¹² are defined as aboveunder formula (IIIc).

A more preferred embodiment of the invention, in the compounds offormula (II), are compounds of the formula (IIb),

wherein

R¹ and R² are defined as above, Z is defined as above; X is O or S, R³is H, methyl, methoxy, CF₃, or OCF₃.

Another more preferred embodiment of the invention, in the compounds offormula (II), are compounds of the formula (IIc),

wherein

X is O or S; R³ is H, methyl, methoxy, CF₃, or OCF₃; Y′ is NR^(2′).

Another more preferred embodiment of the invention, in the compounds offormula (II), are compounds of the formula (IId),

wherein

Z is defined as above; R³ is H, methyl, methoxy, CF₃, or OCF₃; R¹¹,R^(11′) and R¹², R^(12″) are defined as above.

In addition, the present invention provides methods for preparing thecompounds of the invention such as compounds of formula (Ia), (Ib),(Ic), (II), or (III).

The compounds of formula (Ia), (Ib), (Ic), (II), or (III) may beobtained via various methods.

Piperidin-4-yl-thiazole-4-carboxamide can be prepared by various methodsdescribed in the literature. One such example is the oxidation of theappropriate 2,5-dihydrothiazoles as described in Houben-Weyl, 2002, 730.The dihydrothiazoles can also synthesised by methods described in thesame reference or described in You, S., Razavi, H., Kelly, J. W. Angew.Chem. 2003, 115, 87 or Katritzky, A R., Cai, C., Suzuki, K., Singh, S K.J. Org. Chem. 2004, 69, 811-814 and references in both papers.Alternative methods were described by Yasuchika, S. et. al.Heterocycles, Vol. 57, No. 5, 2002.

The compounds of formula (II), (Ic), and (III) carrying a furthersubstituent on the heterocycle can be obtained via various methodsdescribed in Organic Syntheses, Coll. Vol. 9, p. 155; and Vol. 74, p.229; J. Org. Chem., 1975, Vol. 40, No. 10, page 1521, J. Am. Chem. Soc.96:19 Sep. 18, 1974; J. Org. Chem., 1990, 55, 4484-4487; ChemischeBerichte 1968, 101 (1), 302-307; Agricultural Chemistry andBiotechnology, 2002, 45 (1), page 37-42.

One possibility for the synthesis of substitutedbenzimindazole-substituent of formula (Ih) and (III) is described inSynthesis, 2006, 4, 597-602.

One possibility for the synthesis of compounds of formula (IIIa, c andIa, b) (see scheme 1) comprises a step of reacting a compound of formula(V) with a compound of formula (VI) under classical amide couplingconditions, like e.g. HBTU, iPr₂NEt, DMF, 0° C. to r.t. to obtainintermediate (VII). Another alternative for this step might be thereaction of (V) with the corresponding acid chloride of (VI) to yield(VII). In a second step, compound (VII) is saponified with a 1 M NaOHsolution, obtaining the expected acid (VIII) in almost quantitativeyield. This step could be realized under acidic conditions as well.Finally, another amide coupling step (with primary or secondary amines),which works similarily to step 1 described above, completes thesynthesis for compounds of type (IIa, c and IIa, and b).

Compounds dealing with structure (IIIb, d, e, f) and (IIc, d) can besynthesized according to the procedure displayed in scheme 2. Herein, aheterocycle (IX) is reacted with a bromocompound (X), by means of anucleophilic substitution reaction, to gain a bicyclic ester (XI), whichis then saponified under standard and well-known conditions to acid(XII), completing the synthesis with another coupling step as describedin scheme 1 above.

In case of Z=CH, structure (IIIb, d, e, f) and (IIc, d) type compoundscan easily be synthesized following a protocol outlined in scheme 3,wherein a heterocycle (XIII) is converted to compound (XV) by acyclokondensation step. After saponification, (XVI) is coupled with anamine to yield the desired product (IIIb, d, e, f) or (IIc, d).

For the compounds of the formula (I), (Ia), (Ib), (Ic), (II), or (III)above, the term “stereoisomer” means cis/trans or E/Z isomerism. Moreparticularly, the possible double bond(s) present in the varioussubstituent of the compounds of the present invention can be E or Zconfiguration. These pure or impure geometrical isomers, alone or as amixture, form an integral part of the compounds of the formula (I),(Ia), (Ib), (Ic), (II), or (III).

The term “stereoisomer” includes also all the isomeric forms, alone oras mixture, resulting from the presence of one or more axes and/orcentres of symmetry in the molecules, and resulting in the rotation of abeam of polarized light. More particularly, it includes enantiomers anddiastereomers, in pure form or as a mixture.

The compounds of the formula (I), (Ia), (Ib), (Ic), (II), or (III) to beused according to the invention can form salts with inorganic or organicacids or bases. Examples of pharmaceutically acceptable salts comprisewithout limitation non-toxic inorganic or organic salts such as acetatederived from acetic acid, aconitate derived from aconitic acid,ascorbate derived from ascorbic acid, benzoate derived from benzoicacid, cinnamate derived from cinnamic acid, citrate derived from citricacid, embonate derived from embonic acid, enantate derived fromheptanoic acid, formiate derived from formic acid, fumarate derived fromfumaric acid, glutamate derived from glutamic acid, glycolate derivedfrom glycolic acid, chloride derived from hydrochloric acid, bromidederived from hydrobromic acid, lactate derived from lactic acid, maleatederived from maleic acid, malonate derived from malonic acid, mandelatederived from mandelic acid, methanesulfonate derived frommethanesulfonic acid, naphtaline-2-sulfonate derived fromnaphtaline-2-sulfonic acid, nitrate derived from nitric acid,perchlorate derived from perchloric acid, phosphate derived fromphosphoric acid, phthalate derived from phthalic acid, salicylatederived from salicylic acid, sorbate derived from sorbic acid, stearatederived from stearic acid, succinate derived from succinic acid,sulphate derived from sulphuric acid, tartrate derived from tartaricacid, toluene-p-sulfate derived from p-toluene-sulfonic acid and others.Such salts can be produced by methods known to someone of skill in theart and described in the prior art.

Other salts like oxalate derived from oxalic acid, which is notconsidered as pharmaceutically acceptable can be appropriate asintermediates for the production of compounds of the formula (I), (Ia),(Ib), (Ic), (II), or (III) or a pharmaceutically acceptable salt thereofor pharmaceutically acceptable prodrugs, or a stereoisomer thereof.

The invention covers the pharmaceutically acceptable salts, as indicatedabove, but also salts allowing a suitable separation or crystallizationof the compounds of the formula (I), (Ia), (Ib), (Ic), (II), or (III),such as the salts obtained with chiral amines.

The compounds of the formula (I), (Ia), (Ib), (Ic), (II), or (III) abovealso comprise the prodrugs of these compounds.

The term “prodrug” as used herein refers to compounds which onceadministered to the patient are not pharmaceutically active themselves(‘prodrugs’) but which are chemically and/or biologically transformedinto their pharmaceutical active form (compounds of formula (T), (Ia),(Ib), (Ic), (II), or (III)) in vivo, i.e. in the subject to which thecompound is administered.

The compounds according to the invention and medicaments preparedtherewith are generally useful for the treatment of cell proliferationdisorders, for the treatment or prophylaxis of immunological diseasesand conditions (as for instance inflammatory diseases,neuroimmunological diseases, autoimmune diseases or other).

The compounds of the present invention are useful for the treatment ofdiseases which are caused by malignant cell proliferation, such as allforms of solid tumors, leukemias and lymphomas. Therefore the compoundsaccording to the invention and medicaments prepared therewith aregenerally useful for regulating cell activation, cell proliferation,cell survival, cell differentiation, cell cycle, cell maturation andcell death or to induce systemic changes in metabolism such as changesin sugar, lipid or protein metabolism. They can also be used to supportcell generation poiesis, including blood cell growth and generation(prohematopoietic effect) after depletion or destruction of cells, ascaused by, for example, toxic agents, radiation, immunotherapy, growthdefects, malnutrition, malabsorption, immune dysregulation, anemia andthe like or to provide a therapeutic control of tissue generation anddegradation, and therapeutic modification of cell and tissue maintenanceand blood cell homeostasis.

These diseases and conditions include but are not limited to cancer ashematological (e.g. leukemia, lymphoma, myeloma) or solid tumors (forexample breast, prostate, liver, bladder, lung, esophageal, stomach,colorectal, genitourinary, gastrointestinal, skin, pancreatic, brain,uterine, colon, head and neck, cervical, and ovarian, melanoma,astrocytoma, small cell lung cancer, glioma, basal and squameous cellcarcinoma, sarcomas as Kaposi's sarcoma and osteosarcoma) or for thetreatment of diseases which are cured or relieved by the inhibition ofone or several kinases and/or phosphatases.

“Treatment” according to the present invention is intended to meancomplete or partial healing of a disease, or alleviation of a disease orstop of progression of a given disease.

Thus, in one embodiment, the invention relates to the use of thecompounds of the formula (I), (Ia), (Ib), (Ic), (II), or (III) or apharmaceutically acceptable salt or pharmaceutically acceptableprodrugs, or a stereoisomer thereof if desired with appropriateadjuvants and additives for the production of a medicament for thetreatment or prevention of a disease characterized by hyperproliferationof keratinocytes and/or T cells, especially inflammatory disorders andimmune disorders, preferably selected from the group consisting ofAddison's disease, alopecia areata, Ankylosing spondylitis, haemolyticanemia (anemia haemolytica), pernicious anemia (anemia perniciosa),aphthae, aphthous stomatitis, arthritis, arteriosclerotic disorders,osteoarthritis, rheumatoid arthritis, aspermiogenese, asthma bronchiale,auto-immune asthma, auto-immune hemolysis, Bechet's disease, Boeck'sdisease, inflammatory bowel disease, Burkitt's lymphoma, Crohn'sdisease, chorioiditis, colitis ulcerosa, Coeliac disease,cryoglobulinemia, dermatitis herpetiformis, dermatomyositis,insulin-dependent type I diabetes, juvenile diabetes, idiopathicdiabetes insipidus, insulin-dependent diabetes mellisis, autoimmunedemyelinating diseases, Dupuytren's contracture, encephalomyelitis,encephalomyelitis allergica, endophthalmia phacoanaphylactica, enteritisallergica, autoimmune enteropathy syndrome, erythema nodosum leprosum,idiopathic facial paralysis, chronic fatigue syndrome, febrisrheumatica, glomerulo nephritis, Goodpasture's syndrome, Graves'disease, Hamman-Rich's disease, Hashimoto's disease, Hashimoto'sthyroiditis, sudden hearing loss, sensoneural hearing loss, hepatitischronica, Hodgkin's disease, haemoglobinuria paroxysmatica,hypogonadism, ileitis regionalis, iritis, leucopenia, leucemia, lupuserythematosus disseminatus, systemic lupus erythematosus, cutaneouslupus erythematosus, lymphogranuloma malignum, mononucleosis infectiosa,myasthenia gravis, traverse myelitis, primary idiopathic myxedema,nephrosis, ophthalmia symphatica, orchitis granulomatosa, pancreatitis,pemphigus, pemphigus vulgaris, polyarteritis nodosa, polyarthritischronica primaria, polymyositis, polyradiculitis acuta, psoriasis,purpura, pyoderma gangrenosum, Quervain's thyreoiditis, Reiter'ssyndrome, sarcoidosis, ataxic sclerosis, progressive systemic sclerosis,scleritis, sclerodermia, multiple sclerosis, sclerosis disseminata,acquired spenic atrophy, infertility due to antispermatozoan antibodies,thrombocytopenia, idiopathic thrombocytopenia purpura, thymoma, acuteanterior uveitis, vitiligo, AIDS, HIV, SCID and Epstein Barr virusassociated diseases such as Sjorgren's syndrome, virus (AIDS or EBV)associated B cell lymphoma, parasitic diseases such as Leishmania, andimmunesuppressed disease states such as viral infections followingallograft transplantations, AIDS, cancer, chronic active hepatitisdiabetes, toxic chock syndrome and food poisoning.

Furthermore, the invention relates to a method of treatment orprevention of diseases which comprises the administration of aneffective amount of compounds of the (I), (Ia), (Ib), (Ic), (II), or(III) or a pharmaceutically acceptable salt or pharmaceuticallyacceptable prodrugs, or a stereoisomer thereof.

The invention also provides a pharmaceutical composition comprising acompound of formula (I), (Ia), (Ib), (Ic), (II), or (III), in free formor in the form of pharmaceutically acceptable salts and pharmaceuticallyacceptable prodrugs, together with a pharmaceutically acceptable diluentor carrier therefore.

In a preferred embodiment, the invention relates to the use of compoundsof the formula (I), (Ia), (Ib), (Ic), (II), or (III), or apharmaceutically acceptable salt or pharmaceutically acceptable prodrugsor a stereoisomer thereof if desired with appropriate adjuvants andadditives for the production of a medicament for the treatment orprevention of skin diseases in which T cells play a role; especiallypreferably the skin diseases are selected from the group consisting ofpsoriasis, atopic dermatitis, alopecia areata, alopecia totalis,alopecia subtotalis, alopecia universalis, alopecia diffusa, lupuserythematodes of the skin, lichen planus, dermatomyostis of the skin,atopic eczema, morphea, sklerodermia, psoriasis vulgaris, psoriasiscapitis, psoriasis guttata, psoriasis inversa, alopecia areataophiasis-type, androgenetic alopecia, allergic contact eczema,irritative contact eczema, contact eczema, pemphigus vulgaris, pemphigusfoliaceus, pemphigus vegetans, scarring mucosal pemphigoid, bullouspemphgoid, mucous pemphigoid, dermatitis, dermatitis herpetiformisduhring, urticaria, necrobiosis lipoidica, erythema nodosum, lichenvidal, prurigo simplex, prurigo nodularis, prurigo acuta, linear IgAdermatosis, polymorphic light dermatoses, erythema solaris, lichensclerosus et atrophicans, exanthema of the skin, drug exanthema, purpurachronica progressiva, dihidrotic eczema, Eczema, fixed drug exanthema,photoallergic skin reaction, lichen simplex eriorale, dermatitis and“Graft versus Host-Disease”, acne, rosacea, scarring, keloids andvitiligo.

Moreover, the compounds of the present invention can be used for thetreatment of diseases resulting from ischemia and/or reperfusion injuryof organs and/or of parts of the body selected from the group comprisingheart, brain, peripheral limb, kidney, liver, spleen and lung, and/orwherein the endothelial dysfunction is associated with diseases selectedfrom a group comprising infarctions such as myocardial infarction andcritical limb ischemia, and/or wherein the endothelial dysfunction isassociated with diseases selected from the group comprising ischemicdiseases such as peripheral arterial occlusive disease, e.g. criticalleg ischemia, myocardial infarction and ischemic diseases of organs,e.g. of the kidney, spleen, brain and lung.

The compounds of this invention also can be applied for the preventionand the treatment of neurological diseases or disorders (diseases ordisorders associated with the brain and nervous system), including butnot limited to, Alzheimer's disease, Parkinson's disease,Creutzfeld-Jacob Disease, Lewy Body Dementia, amyotrophic lateralsclerosis, stroke, epilepsy, multiple sclerosis, myasthenia gravis,Huntington's Disease, Down's Syndrome, nerve deafness, and Meniere'sdisease.). Other neurological diseases and disorders will be apparent tothose of skill in the art and are encompassed by the definition as usedin this invention.

The compounds of the present invention can further be used for diseasesthat are caused by protozoal infestations in humans and animals. Suchveterinary and human pathogenic protozoas are preferably intracellularactive parasites of the phylum Apicomplexa or Sarcomastigophora,especially Trypanosoma, Plasmodia, Leishmania, Babesia and Theileria,Cryptosporidia, Sacrocystida, Amoebia, Coccidia and Trichomonadia. Theseactive substances or corresponding drugs are especially suitable for thetreatment of Malaria tropica, caused by Plasmodium falciparum, Malariatertiana, caused by Plasmodium vivax or Plasmodium ovale and for thetreatment of Malaria quartana, caused by Plasmodium malariae. They arealso suitable for the treatment of Toxoplasmosis, caused by Toxoplasmagondii, Coccidiosis, caused for instance by Isospora belli, intestinalSarcosporidiosis, caused by Sarcocystis suihominis, dysentery caused byEntamoeba histolytica, Cryptosporidiosis, caused by Cryptosporidiumparvum, Chargas disease, caused by Trypanosoma cruzi, sleeping sickness,caused by Trypanosoma brucei rhodesiense or gambiense, the cutaneous andvisceral as well as other forms of Leishmaniosis. They are also suitablefor the treatment of animals infected by veterinary pathogenic protozoa,like Theileria parva, the pathogen causing bovine East coast fever,Trypanosoma congolense congolense or Trypanosoma vivax vivax,Trypanosoma brucei brucei, pathogens causing Nagana cattle disease inAfrica, Trypanosoma brucei evansi causing Surra, Babesia bigemina, thepathogen causing Texas fever in cattle and buffalos, Babesia bovis, thepathogen causing European bovine Babesiosis as well as Babesiosis indogs, cats and sheep, Sarcocystis ovicanis and ovifelis pathogenscausing Sarcocystiosis in sheep, cattle and pigs, Cryptosporidia,pathogens causing Cryptosporidioses in cattle and birds, Eimeria andIsospora species, pathogens causing Coccidiosis in rabbits, cattle,sheep, goats, pigs and birds, especially in chickens and turkeys. Theuse of the compounds of the present invention is preferred in particularfor the treatment of Coccidiosis or Malaria infections, or for thepreparation of a drug or feed stuff for the treatment of these diseases.This treatment can be prophylactic or curative. In the treatment ofmalaria, the compounds of the present invention may be combined withother anti-malaria agents.

The compounds of the present invention can further be used for theprophylaxis and/or treatment of infectious diseases caused among othersby bacteria and viruses, including opportunistic infections in a mammal,including a human. Said method comprises administering to the mammal anamount of at least one compound of the general formula (I), (Ia), (Ib),(Ic), (II), or (III) and/or pharmaceutically acceptable salts thereof,effective to prevent and/or treat said infectious disease and/oropportunistic infection.

The infectious disease can be selected from the group comprising AIDS,Alveolar Hydatid Disease (AHD, Echinococcosis), Amebiasis (Entamoebahistolytica Infection), Angiostrongylus Infection, Anisakiasis, Anthrax,Babesiosis (Babesia Infection), Balantidium Infection (Balantidiasis),Baylisascaris Infection (Raccoon Roundworm), Bilharzia(Schistosomiasis), Blastocystis hominis Infection (Blastomycosis),Boreliosis, Botulism, Brainerd Diarrhea, Brucellosis, BSE (BovineSpongiform Encephalopathy), Candidiasis, Capillariasis (CapillariaInfection), CFS (Chronic Fatigue Syndrome), Chagas Disease (AmericanTrypanosomiasis), Chickenpox (Varicella-Zoster virus), Chlamydiapneumoniae Infection, Cholera, Chronic Fatigue Syndrome, CJD(Creutzfeldt-Jakob Disease), Clonorchiasis (Clonorchis Infection), CLM(Cutaneous Larva Migrans, Hookworm Infection), Coccidioidomycosis,Conjunctivitis, Coxsackievirus A16 (Hand, Foot and Mouth Disease),Cryptococcosis, Cryptosporidium Infection (Cryptosporidiosis), Culexmosquito (Vector of West Nile Virus), Cutaneous Larva Migrans (CLM),Cyclosporiasis (Cyclospora Infection), Cysticercosis(Neurocysticercosis), Cytomegalovirus Infection (CMV), Dengue/DengueFever, Dipylidium Infection (Dog and Cat Flea Tapeworm), Ebola VirusHemorrhagic Fever, Echinococcosis (Alveolar Hydatid Disease),Encephalitis, Entomoeba coli Infection, Entomoeba dispar Infection,Entomoeba hartmanni Infection, Entomoeba histolytica Infection(Amebiasis), Entomoeba polecki Infection, Enterobiasis (PinwormInfection), Enterovirus Infection (Non-Polio), Epstein-Barr VirusInfection, Escherichia coli Infection, Foodborne Infection, Foot andmouth Disease, Fungal Dermatitis, Gastroenteritis, Group A streptococcalDisease, Group B streptococcal Disease, diseases caused bystaphylococcal infections (Staphylococcus aureus and otherstaphylococcus species), diseases caused by infections with pseudomonasaeruginosa and other pseudomonas species, Burkholderia cepaciainfections, Hansen's Disease (Leprosy), Hantavirus Pulmonary Syndrome,Head Lice Infestation (Pediculosis), Helicobacter pylori Infection,Hematologic Disease, Hendra Virus Infection, Hepatitis, Herpes Zoster(Shingles), HIV Infection, Human Ehrlichiosis, Human Parainfluenza VirusInfection, Influenza, Isosporiasis (Isospora Infection), Lassa Fever,Leishmaniasis, Kala-azar (Kala-azar, Leishmania Infection), Leprosy,Lice (Body lice, Head lice, Pubic lice), Lyme Disease, MarburgHemorrhagic Fever, Measles, Meningitis, Mosquito-borne Diseases,Mycobacterium avium Complex (MAC) Infection, Naegleria Infection,Nosocomial Infections, Nonpathogenic Intestinal Amebae Infection,Onchocerciasis (River Blindness), Opisthorciasis (OpisthorcisInfection), Parvovirus Infection, Plague, PCP (Pneumocystis cariniiPneumonia), Polio, Q Fever, Rabies, Respiratory Syncytial Virus (RSV)Infection, Rheumatic Fever, Rift Valley Fever, River Blindness(Onchocerciasis), Rotavirus Infection, Roundworms Infection,Salmonellosis, Salmonella Enteritidis, Scabies, Shigellosis, Shingles,Sleeping Sickness, Smallpox, Streptococcal Infection, Tapeworm Infection(Taenia Infection), Tetanus, Toxic Shock Syndrome, Tuberculosis, Ulcers(Peptic Ulcer Disease), Valley Fever, Vibrio parahaemolyticus Infection,Vibrio vulnificus Infection, Viral Hemorrhagic Fever, Warts, Waterborneinfectious Diseases, West Nile Virus Infection (West Nile Encephalitis),Whooping Cough, Yellow Fever.

The compounds of formula (I), (Ia), (Ib), (Ic), (II), or (III) and theirpharmacologically acceptable salts can be administered to animals,preferably to mammals, and in particular to humans, dogs and chickens astherapeutics per se, as mixtures with one another or in the form ofpharmaceutical preparations which allow enteral or parenteral use andwhich as active constituent contain an effective dose of at least onecompound of the formula (I), (Ia), (Ib), (Ic), (II), or (III) or a saltthereof, in addition to customary pharmaceutically innocuous excipientsand additives. The compounds of formula (I), (Ia), (Ib), (Ic), (II), or(III) can also be administered in form of their salts, which areobtainable by reacting the respective compounds with physiologicallyacceptable acids and bases.

The production of medicaments containing the compounds of formula (I),(Ia), (Ib), (Ic), (II), or (III) according to the invention and theirapplication can be performed according to well-known pharmaceuticalmethods.

While the compounds of formula (I), (Ia), (Ib), (Ic), (II), or (III)according to the invention for use in therapy may be administered in theform of the raw chemical compound, it is preferred to introduce theactive ingredient, optionally in the form of a physiologicallyacceptable salt in a pharmaceutical composition together with one ormore adjuvants, excipients, carriers, buffers, diluents, and/or othercustomary pharmaceutical auxiliaries. Such salts of the compounds may beanhydrous or solvated.

In a preferred embodiment, the invention provides medicaments comprisingcompounds of formula (I), (Ia), (Ib), (Ic), (II), or (III) according tothe invention, or a pharmaceutically acceptable salt or pharmaceuticallyacceptable prodrugs or a stereoisomer thereof, together with one or morepharmaceutically acceptable carriers thereof, and, optionally, othertherapeutic and/or prophylactic ingredients. The carrier(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not harmful to the recipient thereof.

A medicament of the invention may be those suitable for oral, rectal,bronchial, nasal, topical, buccal, sub-lingual, transdermal, vaginal orparenteral (including cutaneous, subcutaneous, intramuscular,intraperitoneal, intravenous, intraarterial, intracerebral, intraocularinjection or infusion) administration, or those in a form suitable foradministration by inhalation or insufflation, including powders andliquid aerosol administration, or by sustained release systems. Suitableexamples of sustained release systems include semipermeable matrices ofsolid hydrophobic polymers containing the compound of the invention,which matrices may be in form of shaped articles, e.g. films ormicrocapsules.

The compounds according to the invention, together with a conventionaladjuvant, carrier, or diluent, may thus be placed into the form ofmedicament and unit dosages thereof. Such forms include solids, and inparticular tablets, filled capsules, powder and pellet forms, andliquids, in particular aqueous or non-aqueous solutions, suspensions,emulsions, elixirs, and capsules filled with the same, all for oral use,suppositories for rectal administration, and sterile injectablesolutions for parenteral use. Such Medicament and unit dosage formsthereof may comprise conventional ingredients in conventionalproportions, with or without additional active compounds or principles,and such unit dosage forms may contain any suitable effective amount ofthe active ingredient commensurate with the intended daily dosage rangeto be employed.

The compound useable according to the invention can be administered in awide variety of oral and parenteral dosage forms. It will be obvious tothose skilled in the art that the following dosage forms may comprise,as the active component, either a compound of formula (I), (Ia), (Ib),(Ic), (II), or (III) according to the invention or a pharmaceuticallyacceptable salt or stereoisomer thereof.

For preparing a medicament from a compounds of formula (I), (Ia), (Ib),(Ic), (II), or (III) pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavouring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingcapacity in suitable proportions and compacted in the shape and sizedesired. Suitable carriers are magnesium carbonate, magnesium stearate,talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth,methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoabutter, and the like. The term “preparation” is intended to include theformulation of the active compound with encapsulating material ascarrier providing a capsule in which the active component, with orwithout carriers, is surrounded by a carrier, which is thus inassociation with it. Similarly, cachets and lozenges are included.Tablets, powders, capsules, pills, cachets, and lozenges can be used assolid forms suitable for oral administration. For preparingsuppositories, a low melting wax, such as a mixture of fatty acidglyceride or cocoa butter, is first melted and the active component isdispersed homogeneously therein, as by stirring. The molten homogenousmixture is then poured into convenient sized moulds, allowed to cool,and thereby to solidify. Compositions suitable for vaginaladministration may be presented as pessaries, tampons, creams, gels,pastes, foams or sprays containing in addition to the active ingredientsuch carriers as are known in the art to be appropriate. Liquidpreparations include solutions, suspensions, and emulsions, for example,water or water-propylene glycol solutions. For example, parenteralinjection liquid preparations can be formulated as solutions in aqueouspolyethylene glycol solution.

The compounds of formula (I), (Ia), (Ib), (Ic), (II), or (III) accordingto the present invention may thus be formulated for parenteraladministration (e.g. by injection, for example bolus injection orcontinuous infusion) and may be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The compositions may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, andmay contain formulation agents such as suspending, stabilising and/ordispersing agents. Alternatively, the active ingredient may be in powderform, obtained by aseptic isolation of sterile solid or bylyophilization from solution, for constitution with a suitable vehicle,e.g. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavours,stabilising and thickening agents, as desired. Aqueous suspensionssuitable for oral use can be made by dispersing the finely dividedactive component in water with viscous material, such as natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcellulose,or other well known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavours, stabilisers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

In one embodiment of the present invention, the medicament is appliedtopically or systemically or via a combination of the two routes.

In an especially preferred embodiment of the present invention themedicament is applied topically. This reduces possible side effects andlimits the necessary treatment to those areas affected.

Preferably the medicament is prepared in form of an ointment, a gel, aplaster, an emulsion, a lotion, a foam, a cream of a mixed phase oramphiphilic emulsion system (oil/water-water/oil mixed phase), aliposome, a transfersome, a paste or a powder.

Ointments and creams may, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions may be formulated with an aqueous or oily base and willin general also contain one or more emulsifying agents, stabilisingagents, dispersing agents, suspending agents, thickening agents, orcolouring agents.

Compositions suitable for topical administration in the mouth includelozenges comprising the active agent in a flavoured base, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert base such as gelatin and glycerine or sucrose andacacia; and mouthwashes comprising the active ingredient in a suitableliquid carrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Thecompositions may be provided in single or multi-dose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomising spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurised pack with a suitable propellant such as a chlorofluorocarbon(CFC) for example dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of adry powder, for example a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

In compositions intended for administration to the respiratory tract,including intranasal compositions, the compound will generally have asmall particle size for example of the order of 5 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization.

When desired, compositions adapted to give sustained release of theactive ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packaged tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form. Tablets or capsules for oral administration andliquids for intravenous administration and continuous infusion arepreferred compositions.

Further details on techniques for formulation and administration may befound in the latest edition of Remington's Pharmaceutical Sciences(Maack Publishing Co. Easton, Pa.).

Pharmaceutical compositions can also contain two or more compounds ofthe formula (I), (Ia), (Ib), (Ic), (II), or (III) or theirpharmacologically acceptable salts and also other therapeutically activesubstances.

Thus, the compounds of the present invention can be used in the form ofone compound alone or in combination with other active compounds—forexample with medicaments already known for the treatment of theaforementioned diseases, whereby in the latter case a favorableadditive, amplifying effect is noticed. Suitable amounts to beadministered to humans may range from 5 to 500 mg.

To prepare the pharmaceutical preparations, pharmaceutically inertinorganic or organic excipients can be used. To prepare pills, tablets,coated tablets and hard gelatin capsules, for example, lactose, cornstarch or derivatives thereof, talc, stearic acid or its salts, etc. canbe used. Excipients for soft gelatin capsules and suppositories are, forexample, fats, waxes, semi-solid and liquid polyols, natural or hardenedoils etc. Suitable excipients for the production of solutions and syrupsare, for example, water, sucrose, invert sugar, glucose, polyols etc.Suitable excipients for the production of injection solutions are, forexample, water, alcohols, glycerol, polyols or vegetable oils.

The dose can vary within wide limits and is to be suited to theindividual conditions in each individual case. For the above uses theappropriate dosage will vary depending on the mode of administration,the particular condition to be treated and the effect desired. Ingeneral, however, satisfactory results are achieved at dosage rates ofabout 1 to 100 mg/kg animal body weight preferably 1 to 50 mg/kg. Ingeneral, suitable dosage rates for larger mammals, for example humans,may be of the order of from about 10 mg to 3 g/day, convenientlyadministered once, in divided doses 2 to 4 times a day, or in sustainedrelease form.

In general, a daily dose of approximately 10 mg to 5000 mg, preferably50 to 500 mg, per human individual is appropriate in the case of theoral administration. In the case of other administration forms too, thedaily dose is in similar ranges. For topical delivery, depending on thepermeability of the skin, the type and the severity of the disease anddependent on the type of formulation and frequency of application,different concentrations of active compounds within the medicament canbe sufficient to elicit a therapeutic effect by topical application.Preferably the concentration of an active compound or a pharmaceuticallyacceptable salt thereof or a physiologically functional derivative or astereoisomer thereof within a medicament according to the invention isin the range of between 1 μmol/l and 100 mmol/l.

The following examples and figures are included to demonstrate preferredembodiments of the invention. It should be appreciated by those of skillin the art that the techniques disclosed in the examples that followrepresent techniques discovered by the inventors to function well in thepractice of the invention, and thus can be considered preferred modesfor its practice. However, those of skill in the art should, in light ofthe present disclosure, appreciate that many changes can be made in thespecific embodiments that are disclosed without departing from thespirit and scope of the invention as set out in the appended claims. Allreferences cited are incorporated herein by reference.

EXAMPLES

Abbreviations: min, minute(s); h, hour(s); r.t., room temperature; t-,tert-.

NMR spectra: Bruker Avance 300 MHz. The spectra were recorded at 300 MHz(1H-NMR), respectively, using the residual solvent peak as an internalstandard (DMSO-d₆, δ_(H)=2.49; CD₃OD, δ_(H)=3.31; CDCl₃, δ_(H)=7.26;CD₃CN, δ_(H)=1.93; (CD₃)₂CO, δ_(H)=2.05).

Analytical LC/ESI-MS: 2× Waters 600 Multisolvent Delivery System. 50 μlsample loop. Column, Chromolith Speed ROD RP18e (Merck, Darmstadt),50×4.6 mm, with 2 μm prefilter (Merck). Eluent A, H₂O+0.1% HCO₂H; eluentB, MeCN. Gradient, 5% B to 100% B within 5 min; flow, 3 ml/min. WatersLCZ single quadrupol mass spectrometer with electrospray source. MSmethod, MS8minPM-80-800-20V; positive/negative ion mode scanning, m/z80-800 in 1 s; capillary, 3.5 kV; cone voltage, 20 V; multipliervoltage, 400 V; probe and desolvation gas temperature, 120° C. and 350°C., respectively. Waters 2487 Dual λ Absorbance Detector, set to 254 nm.

Preparative HPLC-MS: Waters 600 Multisolvent Delivery System withpreparative pump heads. 2000 μl or 5000 μl sample loop. Column, WatersX-Terra RP18, 7 μm, 19×150 mm with X-Terra RP18 guard cartridge 7 μm,19×10 mm; used at flow rate 20 ml/min or YMC ODS-A, 120 Å, 40×150 mmwith X-Terra RP18 guard cartridge 7 μm, 19×10 mm; used at flow rate 50ml/min. Make-up solvent: MeCN—H₂O—HCO₂H 80:20:0.05 (v:v:v). Eluent A,H₂O+0.1% HCO₂H; eluent B, MeCN. Different linear gradients from 5-100%eluent B, adapted to sample. Injection volume: 500 μl-2000 μl dependingon sample. Waters ZQ single quadrupol mass spectrometer withelectrospray source. Positive or negative ion mode scanning m/z 80-800in 1 s; capillary, 3.5 kV or 3.0 kV; cone voltage, 20 V; multipliervoltage, 400 V; probe and desolvation gas temperature, 120° C. and 350°C., respectively. Waters Fraction Collector II with mass-triggeredfraction collection. Waters 996 photo diode array detector.

Synthesis of 4-(Methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acidt-butyl ester

Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.0 eq, 21.8mmol) was dissolved under inert conditions in 35 ml dryN,N-dimethylformamide. O,N-dimethyl-hydroxylamine hydrochloride (1.03eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) andtriethylamine (1.5 eq, 32.7 mmol) were added. The reaction mixture wascooled to 0° C., N-(3-Dimethylaminopropyl)-N-ethylcarbodiimidhydrochloride (1.0 eq, 21.8 mmol) was added over a period of 10 minutesand the mixture was stirred vigorously at 0° C. for 1 h and at r.t. for18 h.

The solvent was removed under vacuum and the residue was suspended in400 ml ethylacetate. The organic layer was extracted 3 times with 100 mlof 1 M citric acid, aqueous sodium carbonate and twice with 100 mlbrine, dried over MgSO₄ and filtered. The solvent was removed and theresidue was purified by distillation resulting in a yield of 80%.

Synthesis of 4-Formyl-piperidine-1-carboxylic acid t-butyl ester

4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butylester (1.0 eq, 16.4 mmol) was dissolved in 100 ml dry tetrahydrofuraneunder inert atmosphere. This solution was added dropwise over a periodof 1 h to a suspension of lithiumalanate (3.0 eq, 49.6 mmol) in 70 mldry tetrahydrofurane at −50° C. During the adding of the mixture, thetemperature was held at −50° C. and then allowed to warm to 0° C. within3 h.

The mixture was cooled to −78° C. and quenched carefully with 100 ml 1 Mcitric acid. The mixture was warmed up to r.t. and diluted with 400 mlethylacetate. The phases were separated and the aqueous phase wasextracted 3 times with 70 ml ethylacetate. The combined organic layerswere extracted 3 times with 100 ml 1 M citric acid, aqueous sodiumcarbonate and 2 times with 100 ml brine, dried over MgSO₄ and filtrated.The solvent was removed and the residue was purified by distillationresulting in a yield of 85%

Synthesis of4-(4-Ethoxycarbonyl-4,5-dihydro-thiazol-2-yl)-piperidine-1-carboxylicacid t-butyl ester

4-formyl-piperidine-1-carboxylic acid tert-butyl ester (1.0 eq, 13 mmol)was dissolved under inert conditions in 40 ml toluene. To this solutionL-cystein ethylester hydrochloride (1.6 eq, 21 mmol) and triethylamine(1.6 eq, 21 mmol) were added. The mixture was refluxed for 14 h. Thegenerated water was removed with a Dean & Stark trap.

The solvent was removed and the residue was dissolved in 100 mlethylacetate. The organic layer was extracted 3 times with 50 ml 1 Mcitric acid, aqueous potassium hydrogen carbonate and 2 times with 50 mlbrine, dried over MgSO₄ and filtrated. The solvent was removed and theresidue was purified by silica gel chromatography using a PE/EA 4:1gradient. Yield: 75%

Synthesis of 4-(4-Ethoxycarbonyl-thiazol-2-yl)-piperidine-1-carboxylicacid t-butyl ester

4-(4-Ethoxycarbonyl-4,5-dihydro-thiazol-2-yl)-piperidine-1-carboxylicacid tert-butyl ester (1.0 eq, 8.7 mmol) was solved in 160 ml tolueneunder inert conditions. To this solution MnO₂ (15.0 eq, 130 mmol) wasadded. The reaction was heated to 70° C. under stirring for 5 h. Themixture was filtered over celite and the filtration agent was washed 3times with 30 ml toluene and ethylacetate. The combined organic layerswere distilled in vacuo. The residue was purified by silica gelchromatography using a DCM/MeOH 95:5 gradient. Yield: 30%.

C-Terminal Functionalisation

4-(4-Ethoxycarbonyl-thiazol-2-yl)-piperidine-1-carboxylic acidtert-butyl ester (1.0 eq, 2.9 mmol) was dissolved under inert gas in 40ml dioxane. Under stirring 1.5 ml aqueous 2 N NaOH was added dropwiseover a period of 10 min. Afterwards the mixture was stirred for 2 h atr.t.

The reaction was neutralized with 2 N HCl and the solvent was evaporatedin vacuo. The residue was dissolved in 50 ml ethylacetate. The organiclayer was extracted 3 times with 10 ml of 1 M citric acid and water,dried over MgSO₄ and filtered. The solvent was removed and the residuewas dried in vacuo. Yield 95%

4-(4-Carboxy-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester(1 eq) was dissolved under inert conditions in dry dimethylacetamide(0.03 mmol/ml). To this solution aryl- or alkylamine (1 eq),diisopropylethylamine (2 eq) andO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2eq) was added. The reaction mixture was stirred for 12 h at r.t.

The solvent was removed in vacuo and the residue was dissolved inethylacetate. The organic layer was extracted 3 times with 1 M citricacid, aqueous potassium hydrogen carbonate and 2 times with brine, driedover MgSO₄ and filtered. The solvent was removed and the residue waspurified by silica gel chromatography using a DCM/MeOH 95:5 gradient.Yield: 40-80%

N-Terminal Functionalisation

The N-protected substrate was treated under inert condition with 4 MHCl/dioxane (conc. 0.03 mmol substrate in 1 mL HCl/dioxane) and wasstirred for 2 h at r.t.

The solvent was removed in vacuo to yield the HCl salt of the free aminewithout further purification.

The free amino compound (1 eq) was dissolved under inert conditions indry dimethylacetamide (0.03 mmol/ml). To this solution aryl- oralkylcarboxylic acid (1 eq), diisopropylethylamine (2 eq) andO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2eq) was added in this sequence and the reaction mixture was stirred for12 h at r.t.

The solvent was removed in vacuo and the residue was dissolved inethylacetate. The organic layer was extracted 3 times with 1 M citricacid, aqueous potassium hydrogen carbonate and 2 times with brine, driedover MgSO₄ and filtered. The solvent was removed and the residue waspurified by silica gel chromatography using a DCM/MeOH 95:5 gradient.Yield: 40-80%

General Synthesis for Compounds of Type (III) and (II)

Procedure for the Synthesis of Compounds of Type (IIIa), (IIIc), (IIa)and (IIb)

7.3×10⁻⁴ mol of the benzoic acid derivative (VI) was dissolved in 5 mlDMF and 1 eq. of Hünig's base was added, stirring the reaction mixturefor a few minutes, followed by the addition of 1 eq. of HBTU and furtherstirring at r.t. for 2 min. Afterwards 1 eq.2-Amino-thiazole-4-carboxylic acid ethyl ester was added, stirring themixture overnight at the same temperature. Subsequently, the solvent wasremoved by filtration and the residue redissolved in 5 ml dioxane andtreated with 0.5 ml of a 1M NaOH solution. After the reaction wascomplete, the pH was decreased to 1-2 with a 1M HCl solution and theprecipitated product (VII) filtered and dried in vacuo. For the nextstep, intermediate (VII) was dissolved in 3 ml DMF and 1 eq. of Hu-nig'sbase was added, stirring the reaction mixture for a few minutes,followed by the addition of 1 eq. of HBTU and further stirring at r.t.for 2 min. Afterwards 1 eq. the amino component was added, stirring themixture overnight at the same temperature. Subsequently, the solvent wasremoved by filtration and the crude product redissolved in 10 ml ethylacetate, washed twice with 10 ml citric acid (1M solution), 10 ml sat.NaHCO₃ solution and 10 ml water. The organic phase was then evaporatedand the residue dried over MgSO₄. The solvent was removed and finalpurification was realised by preparative HPLC as described above.

As a second variant for the first step, the corresponding acid chloridederivative of (VI) could be reacted with the2-Amino-thiazole-4-carboxylic acid ethyl ester (1:1) using 1.1 eq. ofHu-nig's base.

Procedure for the Synthesis of Compounds of Type (IIIb, d, e, j) and(IIc, d)

6.3×10⁻⁴ mol of 2-Bromo-thiazole-4-carboxylic acid ethyl ester (X) wasdissolved in 10 ml THF together with 2.2 eq. of the respectivepiperazine (IX), allowing to reflux overnight. Afterwards the solventwas removed in vacuo and the residue purified by pTLC (PE/EE 2/1).

The second and the third step of the reaction were accomplished asdescribed above under the procedure for the synthesis of compounds oftype (IIIa) and (IIIc).

For as synthesis-protocol of type (IIIb, d, e, f and IIc, d) compoundswith Z=CH, see WO 2004/058750.

Examplary compounds of formula (I) of the present invention include, butare not limited to, the followings:

LC/(+)- Cp. Name Mass ESI-MS: ¹H-NMR 1 [4-(1H-Indol-3-yl)-piperidin- 501502 [M + H]⁺ δ = 1.69-2.04 (m, 4H, 2 CH₂), 1-yl]-{2-[1-(pyrazine-2-2.07-2.24 (m, 4H, 2 CH₂), carbonyl)-piperidin-4-yl]- 2.96-3.4 (m, 6H, 2CH₂, 2 CH), thiazol-4-yl}-methanone 4.05-4.91 (m, 4H, 2 CH₂), 6.99-7.78(m, 6H, CH_(Ar)), 8.01 (s, 1H, NH), 8.5-8.9 (m, 3H, CH_(Ar)). 24-[5-(4-{4-[4-(1H-Indol-3-yl)- 621 622 [M + H]⁺ piperidine-1-carbonyl]-thiazol-2-yl}-piperidin-1-yl)- 5-oxo-pentyl]-tetrahydro-thieno[3,4-d]imidazol-2-one 3 4-[4-(4-Benzhydryl- 547 548 [M + H]⁺piperazine-1-carbonyl)- thiazol-2-yl]-piperidine-1- carboxylic acidtert-butyl ester 4 2-Phenyl-1-(4-{4-[4-(3- 543 544 [M + H]⁺ δ =1.48-1.69 (m, 2H, CH₂), trifluoromethyl-phenyl)- 2.02-2.13 (m, 2H, CH₂),piperazine-1-carbonyl]- 2.70-2.9 (m, 2H, CH₂),thiazol-2-yl}-piperidin-1-yl)- 3.22-3.38 (m, 5H, 2 CH₂), 1 CH), 3.74 (s,ethanone 2H, CH₂), 4.51-4.60 (m, 2H, 1 CH₂), 7.06-7.91 (m, 10H CH_(Ar)).5 3-[2-(4-{4-[4-(1H-Indol-3-yl)- 597 598 [M + H]⁺piperidine-1-carbonyl]- thiazol-2-yl}-piperidin-1-yl)-2-oxo-ethyl]-5-methoxy- indan-1-one 6 2-(4-Fluoro-phenyl)-1-(4-{4- 561562 [M + H]⁺ δ = 1.58-1.7 (m, 2H, CH₂), [4-(3-trifluoromethyl-phenyl)-2.06-2.18 (m, 2H, CH₂), piperazine-1-carbonyl]- 2.75 (s, 2H, CH₂)2.78-2.9 (m, 2H, thiazol-2-yl}-piperidin-1-yl)- CH₂), 3.27-3.38 (m, 5H,2 ethanone CH₂, 1 CH), 4.5-4.61 (m, 2H, CH₂), 7.02-7.94 (m, 9H CH_(Ar)).7 2,2-Diphenyl-1-(4-{4-[4-(3- 619 620 [M + H]⁺ δ = 1.3-1.75 (m, 2H, CH₂)trifluoromethyl-phenyl)- 1.94-2.19 (m, 2H, CH₂), piperazine-1-carbonyl]-2.9-3.02 (m, 2H, CH₂) thiazol-2-yl}-piperidin-1-yl)- 3.18-3.43 (m, 6H, 2CH, 2 CH₂) ethanone 4.18-4.7 (m, 2H, CH₂), 7.11-7.95 (m, 15H, CH_(Ar)).8 1-(4-{4-[4-(1H-Indol-3-yl)- 603 604 [M + H]⁺ piperidine-1-carbonyl]-thiazol-2-yl}-piperidin-1-yl)- 3,3-diphenyl-propan-1-one 94-{4-[4-(3-Trifluoromethyl- 525 526 [M + H]⁺ δ = 1.45 (s, 9H, 3 CH₃),phenyl)-piperazine-1- 1.65-1.78 (m, 2H, CH₂), carbonyl]-thiazol-2-yl}-2.05-2.18 (m, 2H, CH₂), 2.91-3.03 (m, 2H, piperidine-1-carboxylic acidCH₂), 3.29 (m_(c), 1H, CH), tert-butyl ester 3.38 (m_(c), 1H, 2 CH₂)4.10-4.19 (m, 2H, CH₂), 7.10-7.96 (m, 5H, CH_(Ar)) 10(2-Piperidin-4-yl-thiazol-4- 424 425 [M + H]⁺ yl)-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 11 {2-[1-(4,7-Dimethyl- 569 570 [M +H]⁺ δ = 1.75-2.07 (m, 4H, 2 CH₂), pyrazolo[5,1-c][1,2,4]triazine-2.08-2.42 (m, 4H, 2 CH₂), 3-carbonyl)-piperidin-4-yl]- 2.63 (s, 3H,CH₃), 2.87 (s, 3H, thiazol-4-yl}-[4-(1H-indol-3- CH₃), 2.94-3.4 (m, 6H,2 CH₂, yl)-piperidin-1-yl]-methanone 2 CH), 3.83 (m_(C), 1H, CH₂),4.44-4.6 (m, 1H, CH₂) 4.84 (m_(c), 2H, CH₂), 6.98-7.79 (m, 7H, CH_(Ar)),8.02 (s, 1H, NH). 12 1-(4-{4-[4-(1H-Indol-3-yl)- 513 514 [M + H]⁺ δ =1.65-1.93 (m, 4H, 2 CH₂), piperidine-1-carbonyl]- 1.96-2.24 (m, 4H, 2CH₂), thiazol-2-yl}-piperidin-1-yl)- 2.77-2.91 (m, 2H, CH₂),2-phenyl-ethanone 2.93-3.05 (m, 1H, CH₂), 3.07-3.2 (m, 2H, 2 CH)3.25-3.34 (m, 1H, CH₂), 3.76 (s, 2H, CH₂), 3.94 (m_(c), 1H, CH₂),4.43-4.57 (m, 1H, CH₂), 4.66 (m_(c), 1H, CH₂), 4.75-4.90 (m, 1H, CH₂),6.98-7.75 (m, 11H, CH_(Ar)), 7.98 (s, 1H, NH). 135-Methoxy-3-[2-oxo-2-(4-{4- 627 628 [M + H]⁺[4-(3-trifluoromethyl-phenyl)- piperazine-1-carbonyl]-thiazol-2-yl}-piperidin-1-yl)- ethyl]-indan-1-one 141-(4-Fluoro-phenyl)-2-(4-{4- 531 532 [M + H]⁺ δ = 1.58-1.85 (m, 4H, 2CH₂), [4-(1H-indol-3-yl)-piperidine- 2.07-2.19 (m, 4H, 2 CH₂),1-carbonyl]-thiazol-2-yl}- 2.64-3.64 (m, 6H, 2 CH₂, 2piperidin-1-yl)-ethanone CH), 3.97 (m_(C), 1H, CH₂), 4.41 (m_(C), 2H,CH₂) 4.49-4.7 (m, 1H, CH₂) 5.48 (s, 2H, CH₂), 6.84-7.71 (m, 10HCH_(Ar)). 15 3-Phenyl-1-(4-{4-[4-(3- 553 554 [M + H]⁺ δ = 1.71-1.97 (m2H, CH₂), trifluoromethyl-phenyl)- 2.20-2.35 (m, 2H, CH₂),piperazine-1-carbonyl]- 3.02 (m_(c), 1H, CH) 3.42-3.55 (m, 6H,thiazol-2-yl}-piperidin-1-yl)- 2 CH₂), 4.51-4.61 (m, 2H, propynone CH₂),7.2-8.0 (m, 9H, CH_(Ar)). 16 3,3-Diphenyl-1-(4-{4-[4-(3- 633 634 [M +H]⁺ δ = 1.44-1.59 (m, 2H, CH₂) trifluoromethyl-phenyl)- 2.04-2.12 (m,2H, CH₂), piperazine-1-carbonyl]- 2.7-2.83 (m, 2H, CH₂),thiazol-2-yl}-piperidin-1-yl)- 3.08-3.34 (m, 4H, 2 CH, CH₂),propan-1-one 3.34-3.41 (m, 4H, 2 CH₂), 4.46-463 (m, 2H, CH₂), 7.11-7.95(m, 15H, CH_(Ar)). 17 {2-[1-(Pyrazine-2-carbonyl)- 531 532 [M + H]⁺ δ =1.83-1.99 (m, 2H, CH₂), piperidin-4-yl]-thiazol-4-yl}- 2.07-2.35 (m, 2H,CH₂), [4-(3-trifluoromethyl-phenyl)- 2.73-2.95 (m, 2H, CH₂), 3.13(m_(c), 1H, piperazin-1-yl]-methanone CH), 3.33-3.44 (m, 4H, 2 CH₂),4.6-4.74 (m, 2H, CH₂), 7.11-8.88 (m, 8H, CH_(Ar)). 18{2-[1-(4,7-Dimethyl- 599 600 [M + H]⁺ pyrazolo[5,1-c][1,2,4]triazine-3-carbonyl)-piperidin-4-yl]- thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone 194-(4-{2-[4-(1H-Indol-3-yl)- 495 496 [M + H]⁺ δ = 1.46 (s 9H 3 CH₃),piperidin-1-carbonyl]}- 1.67-1.92 (m, 4H, 2 CH₂),thiazol-2-yl)-piperidine-1- 2.06-2.23 (m, 4H, 2 CH₂), carboxylic acidtert-butyl ester 2.84-2.95 (m, 2H, 1 CH₂), 2.97-3.08 (m, 1H, 1 CH₂),3.1-3.22 (m, 2H, 2 CH) 3.23-3.36 (m, 1H, 1 CH₂), 4.11-4.23 (m, 2H, 1CH₂), 4.5-4.91 (m, 2H 1 CH₂), 6.96-7.77 (m, 6H CH_(Ar)), 7.98 (s 1H,NH). 20 1-{4-[4-(4-Benzhydryl- 583 584 [M + H]⁺ piperazine-1-carbonyl)-thiazol-2-yl]-piperidin-1-yl}- 2-(4-fluoro-phenyl)-ethanone 21(4-Benzhydryl-piperazin-1- 621 622 [M + H]⁺ yl)-{2-[1-(4,7-dimethyl-pyrazolo[5,1-c][1,2,4]triazine- 3-carbonyl)-piperidin-4-yl]-thiazol-4-yl}-methanone 22 (4-Benzhydryl-piperazin-1- 447 448 [M + H]⁺yl)-(2-piperidin-4-yl-thiazol-4- yl)-methanone 23 1-{4-[4-(4-Benzhydryl-565 566 [M + H]⁺ δ = 1.35 (m_(C), 1H, CH₂), piperazine-1-carbonyl)- 1.60(m_(C), 1H, CH₂), 1.93 (m_(C), 2H, thiazol-2-yl]-piperidin-1-yl}- CH₂),2.37 (m_(C), 4H, 2 CH₂), 2-phenyl-ethanone 2.71 (m_(C), 1H, CH₂),2.97-3.12 (m, 2H, CH₂, CH), 3.67 (s, 2H, CH₂), 3.69-3.91 (m, 5H, 6 CH₂),4.18 (s, 1H, CH), 4.58 (m_(C), 1H, CH₂), 7.09-7.68 (m, 16H, CH_(Ar)). 243-(2-{4-[4-(4-Benzhydryl- 649 650 [M + H]⁺ piperazine-1-carbonyl)-thiazol-2-yl]-piperidin-1-yl}- 2-oxo-ethyl)-5-methoxy- indan-1-oneExamplary compounds of formula (I) of the present invention include, butare not limited to, the followings:

LC/(+)-ESI- Biological Cp. Name Mass MS: activity¹⁾ 29{2-[1-(2,5-Dimethoxy-phenyl)-piperidin-4- 560 561 [M + H]⁺ ++yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 35{2-[1-(3,3-Diphenyl-propyl)-piperidin-4- 618 619 [M + H]⁺ +++yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 48 {4-[1-(4-Fluoro-benzyl)-1H- 692 693[M + H]⁺ +++ benzoimidazol-2-yl]-piperazin-1-yl}-{2-[1-(2-trifluoromethoxy-benzoyl)-piperidin-4- yl]-thiazol-4-yl}-methanone 704-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 553 554 [M + H]⁺ ++piperazine-1-carbonyl]-thiazol-2-yl}-piperidine-1-carbonyl)-benzonitrile 96[4-(1H-Benzoimidazol-2-yl)-piperazin-1- 618 619 [M + H]⁺ +++yl]-{2-[1-(2-trifluoromethoxy-benzoyl)-piperidin-4-yl]-thiazol-4-yl}-methanone 97[4-(5-Methoxy-1H-benzoimidazol-2-yl)- 583 584 [M + H]⁺ +piperazin-1-yl]-{2-[1-(2-trifluoromethoxy-benzoyl)-piperidin-4-yl]-thiazol-4-yl}- methanone 98{4-[1-(4-Fluoro-benzyl)-1H- 692 693 [M + H]⁺ +++benzoimidazol-2-yl]-piperazin-1-yl}-{2-[1-(2-trifluoromethoxy-benzoyl)-piperidin-4- yl]-thiazol-4-yl}-methanone107 [2-(1-Pyridin-4-ylmethyl-piperidin-4-yl)- 515 516 [M + H]⁺ +thiazol-4-yl]-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone108 [2-(1-Pyridin-3-ylmethyl-piperidin-4-yl)- 446 447 [M + H]⁺ +thiazol-4-yl]-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone109 {2-[1-(2-Trifluoromethoxy-benzyl)- 598 599 [M + H]⁺ +piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 1102-[1-(2-Trifluoromethoxy-benzoyl)- 647 648 [M + H]⁺ +piperidin-4-yl]-thiazole-4-carboxylic acid bis-(4-chloro-benzyl)-amide111 (4-Benzotriazol-1-yl-piperidin-1-yl)-{2-[1- 584 585 [M + H]⁺ +(2-trifluoromethoxy-benzoyl)-piperidin-4- yl]-thiazol-4-yl}-methanone112 4-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 525 526 [M + H]⁺ +piperazine-1-carbonyl]-thiazol-2-yl}- piperidin-1-yl)-benzonitrile 1134-{4-[4-(3-Trifluoromethyl-phenyl)- 468 469 [M + H]⁺ +piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carboxylic acid 115{2-[1-(3-Trifluoromethoxy-benzyl)- 598 599 [M + H]⁺ ++piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 117{2-[1-(4-Methanesulfonyl-phenyl)- 578 579 [M + H]⁺ +piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 118[4-(3-Trifluoromethyl-phenyl)-piperazin-1- 569 570 [M + H]⁺ +yl]-[2-(4′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)- thiazol-4-yl]-methanone 119[2-(1-Phenyl-piperidin-4-yl)-thiazol-4-yl]- 500 501 [M + H]⁺ +[4-(3-trifluoromethyl-phenyl)-piperazin-1- yl]-methanone 120[2-(1-Benzyl-piperidin-4-yl)-thiazol-4-yl]- 509 510 [M + H]⁺ +[4-(4,6-dimethoxy-[1,3,5]triazin-2-yl)- piperazin-1-yl]-methanone 121{2-[1-(4-Bromo-benzyl)-piperidin-4-yl]- 587 588 [M + H]⁺ +thiazol-4-yl}-[4-(4,6-dimethoxy- [1,3,5]triazin-2-yl)-piperazin-1-yl]-methanone 122 [2-(1-Pyrazin-2-yl-piperidin-4-yl)-thiazol- 502 503 [M +H]⁺ + 4-yl]-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone 123[2-(3,4,5,6-Tetrahydro-2H- 501 502 [M + H]⁺ ++[1,2′]bipyridinyl-4-yl)-thiazol-4-yl]-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 124(4-{4-[4-(2-Methylsulfanyl-pyrimidin-4- 592 593 [M + H]⁺ +yl)-piperazine-1-carbonyl]-thiazol-2-yl}-piperidin-1-yl)-(2-trifluoromethoxy- phenyl)-methanone 1261-(4-{4-[4-(4,6-Dimethoxy-[1,3,5]triazin-2- 555 556 [M + H]⁺ +yl)-piperazine-1-carbonyl]-thiazol-2-yl}-piperidin-1-yl)-2-(4-fluoro-phenyl)- ethanone 127[4-(4,6-Dimethoxy-[1,3,5]triazin-2-yl)- 607 608 [M + H]⁺ +piperazin-1-yl]-{2-[1-(2-trifluoromethoxy-benzoyl)-piperidin-4-yl]-thiazol-4-yl}- methanone 129(4-{4-[4-(7H-Purin-6-yl)-piperazine-1- 586 587 [M + H]⁺ +carbonyl]-thiazol-2-yl}-piperidin-1-yl)-(2-trifluoromethoxy-phenyl)-methanone 130(4-{4-[4-(2,6-Dimethoxy-pyrimidin-4-yl)- 606 607 [M + H]⁺ +piperazine-1-carbonyl]-thiazol-2-yl}-piperidin-1-yl)-(2-trifluoromethoxy- phenyl)-methanone 1452-[1-(2-Trifluoromethoxy-benzoyl)- 556 557 [M + H]⁺ +piperidin-4-yl]-thiazole-4-carboxylic acid[1-(1H-indol-2-yl)-ethyl]-methyl-amide 1472-[1-(2-Trifluoromethoxy-benzoyl)- 602 603 [M + H]⁺ +piperidin-4-yl]-thiazole-4-carboxylic acidmethyl-(2-morpholin-4-yl-1-phenyl-ethyl)- amide 1482-[1-(2-Trifluoromethoxy-benzoyl)- 533 534 [M + H]⁺ ++piperidin-4-yl]-thiazole-4-carboxylic acidbenzyl-(2-hydroxy-ethyl)-amide 149 2-[1-(2-Trifluoromethoxy-benzoyl)-593 594 [M + H]⁺ + piperidin-4-yl]-thiazole-4-carboxylic acidbenzyl-phenethyl-amide 151 (4-{4-[4-(3-Chloro-phenyl)-piperazine-1- 578579 [M + H]⁺ + carbonyl]-thiazol-2-yl}-piperidin-1-yl)-(2-trifluoromethoxy-phenyl)-methanone 152[4-(4,6-Dimethoxy-[1,3,5]triazin-2-yl)- 419 420 [M + H]⁺ ++piperazin-1-yl]-(2-piperidin-4-yl-thiazol-4- yl)-methanone 153{2-[1-(2,4-Dimethoxy-phenyl)-piperidin-4- 560 561 [M + H]⁺ +yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 154 {2-[1-(4-Trifluoromethoxy-phenyl)-584 585 [M + H]⁺ + piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 155[4-(3-Trifluoromethyl-phenyl)-piperazin-1- 568 569 [M + H]⁺ +yl]-{2-[1-(4-trifluoromethyl-phenyl)-piperidin-4-yl]-thiazol-4-yl}-methanone 156[2-(1-Benzo[1,3]dioxol-5-yl-piperidin-4- 544 545 [M + H]⁺ +yl)-thiazol-4-yl]-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 157{2-[1-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)- 558 559 [M + H]⁺ +piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 158{2-[1-(2-Methoxy-phenyl)-piperidin-4-yl]- 530 531 [M + H]⁺ +thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone159 {2-[1-(3,4-Dimethoxy-phenyl)-piperidin-4- 560 561 [M + H]⁺ +yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 164{2-[1-(2,6-Dimethoxy-pyrimidin-4-yl)- 562 563 [M + H]⁺ ++piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 165{2-[1-(2-Bromo-benzyl)-piperidin-4-yl]- 592 593 [M + H]⁺ +thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone166 4-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 539 540 [M + H]⁺ +piperazine-1-carbonyl]-thiazol-2-yl}- piperidin-1-ylmethyl)-benzonitrile167 [2-(1-Biphenyl-4-ylmethyl-piperidin-4-yl)- 590 591 [M + H]⁺ +thiazol-4-yl]-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone168 {2-[1-(2,6-Difluoro-benzyl)-piperidin-4-yl]- 550 551 [M + H]⁺ +thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone169 {2-[1-(4-Trifluoromethyl-benzyl)-piperidin- 582 583 [M + H]⁺ +4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 170{2-[1-(4-Fluoro-benzyl)-piperidin-4-yl]- 532 533 [M + H]⁺ +thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone171 {2-[1-(2-Chloro-4-fluoro-benzyl)-piperidin- 566 567 [M + H]⁺ +4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 172 {2-[1-(4-Trifluoromethoxy-benzyl)-598 599 [M + H]⁺ + piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 173{2-[1-(3-Methoxy-benzyl)-piperidin-4-yl]- 544 545 [M + H]⁺ +thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone174 {2-[1-(4-Bromo-benzyl)-piperidin-4-yl]- 592 593 [M + H]⁺ +thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone175 {2-[1-(3,5-Bis-trifluoromethyl-benzyl)- 650 651 [M + H]⁺ +piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 176{2-[1-(4,6-Dimethoxy-[1,3,5]triazin-2-yl)- 563 564 [M + H]⁺ +piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 177[2-(1-Benzyl-piperidin-4-yl)-thiazol-4-yl]- 514 515 [M + H]⁺ +[4-(3-trifluoromethyl-phenyl)-piperazin-1- yl]-methanone 178{2-[1-(3-Methoxy-phenyl)-piperidin-4-yl]- 530 531 [M + H]⁺ +thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone180 2-(4-Fluoro-phenyl)-1-{4-[4-(4-phenyl- 492 493 [M + H]⁺ +piperazine-1-carbonyl)-thiazol-2-yl]- piperidin-1-yl}-ethanone 1812-(4-Fluoro-phenyl)-1-(4-{4-[4-(5- 600 601 [M + H]⁺ +trifluoromethyl-benzotriazol-1-yl)-piperidine-1-carbonyl]-thiazol-2-yl}- piperidin-1-yl)-ethanone 1821-{4-[4-(4-Benzotriazol-1-yl-piperidine-1- 532 533 [M + H]⁺ +carbonyl)-thiazol-2-yl]-piperidin-1-yl}-2- (4-fluoro-phenyl)-ethanone183 2-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 573 574 [M + H]⁺ +piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carbonyl)-nicotinicacid 184 2-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 616 617 [M + H]⁺ +piperazine-1-carbonyl]-thiazol-2-yl}-piperidine-1-carbonyl)-terephthalic acid 1852-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 572 573 [M + H]⁺ +piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carbonyl)-benzoicacid 186 3-Hydroxy-2-(4-{4-[4-(3-trifluoromethyl- 588 589 [M + H]⁺ +phenyl)-piperazine-1-carbonyl]-thiazol-2-yl}-piperidine-1-carbonyl)-benzoic acid 1874,5-Dichloro-2-(4-{4-[4-(3-trifluoromethyl- 640 641 [M + H]⁺ +phenyl)-piperazine-1-carbonyl]-thiazol-2-yl}-piperidine-1-carbonyl)-benzoic acid 1882-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 562 563 [M + H]⁺ +piperazine-1-carbonyl]-thiazol-2-yl}-piperidine-1-carbonyl)-cyclopent-1- enecarboxylic acid 1892-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 578 579 [M + H]⁺ +piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carbonyl)-cyclohexanecarboxylic acid 190 2-(4-{4-[4-(3-Trifluoromethyl-phenyl)-576 577 [M + H]⁺ + piperazine-1-carbonyl]-thiazol-2-yl}-piperidine-1-carbonyl)-cyclohex-1- enecarboxylic acid 1914-Oxo-4-(4-{4-[4-(3-trifluoromethyl- 522 523 [M + H]⁺ +phenyl)-piperazine-1-carbonyl]-thiazol-2-yl}-piperidin-1-yl)-but-2-enoic acid 192{2-[1-(3,5-Dimethyl-isoxazole-4-sulfonyl)- 583 584 [M + H]⁺ +piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 193[2-(1-Pentafluorobenzenesulfonyl- 654 655 [M + H]⁺ +piperidin-4-yl)-thiazol-4-yl]-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 194{2-[1-(Thiophene-2-sulfonyl)-piperidin-4- 570 571 [M + H]⁺ +yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 195{2-[1-(2-Chloro-4-fluoro-benzenesulfonyl)- 616 617 [M + H]⁺ +piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 196{2-[1-(2-Bromo-benzenesulfonyl)- 642 643 [M + H]⁺ +piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 197{2-[1-(6-Chloro-imidazo[2,1-b]thiazole-5- 644 645 [M + H]⁺ +sulfonyl)-piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 198[2-(1-Phenylmethanesulfonyl-piperidin-4- 578 579 [M + H]⁺ +yl)-thiazol-4-yl]-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 199 {2-[1-(4-Bromo-benzenesulfonyl)-642 643 [M + H]⁺ + piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 200{2-[1-(2,4-Dichloro-benzenesulfonyl)- 632 633 [M + H]⁺ +piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 201{2-[1-(3,5-Bis-trifluoromethyl- 700 701 [M + H]⁺ ++benzenesulfonyl)-piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone 202{2-[1-(5-Chloro-2-methoxy- 628 629 [M + H]⁺ ++benzenesulfonyl)-piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone 203{2-[1-(5-Bromo-thiophene-2-sulfonyl)- 648 649 [M + H]⁺ +piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 204{2-[1-(Toluene-4-sulfonyl)-piperidin-4-yl]- 578 579 [M + H]⁺ +thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone205 {2-[1-(4-Trifluoromethoxy- 648 649 [M + H]⁺ +benzenesulfonyl)-piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone 206{2-[1-(4-Chloro-benzenesulfonyl)- 598 599 [M + H]⁺ +piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 207N-[4-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 621 622 [M + H]⁺ +piperazine-1-carbonyl]-thiazol-2-yl}-piperidine-1-sulfonyl)-phenyl]-acetamide 208[2-(1-Benzenesulfonyl-piperidin-4-yl)- 564 565 [M + H]⁺ +thiazol-4-yl]-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone209 {2-[1-(3-Methoxy-benzoyl)-piperidin-4-yl]- 558 559 [M + H]⁺ +thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone210 {2-[1-(4-Methyl-3,4-dihydro-2H- 599 600 [M + H]⁺ ++benzo[1,4]oxazine-7-carbonyl)-piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 211{2-[1-(Quinoxaline-6-carbonyl)-piperidin- 580 581 [M + H]⁺ +4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 212{2-[1-(Thiophene-2-carbonyl)-piperidin-4- 534 535 [M + H]⁺ +yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 213{2-[1-(Benzo[b]thiophene-2-carbonyl)- 584 585 [M + H]⁺ ++piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 2143-Phenyl-1-(4-{4-[4-(3-trifluoromethyl- 554 555 [M + H]⁺ ++phenyl)-piperazine-1-carbonyl]-thiazol-2- yl}-piperidin-1-yl)-propenone215 {2-[1-(3-Fluoro-4-trifluoromethyl- 614 615 [M + H]⁺ +++benzoyl)-piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 216{2-[1-(5-tert-Butyl-2-methyl-2H-pyrazole- 588 589 [M + H]⁺ ++3-carbonyl)-piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1- yl]-methanone 217{2-[1-(2,3-Dihydro-benzo[1,4]dioxine-2- 586 587 [M + H]⁺ +++carbonyl)-piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 218(2-{1-[5-(4-Chloro-phenyl)-2- 696 697 [M + H]⁺ +++trifluoromethyl-furan-3-carbonyl]- piperidin-4-yl}-thiazol-4-yl)-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 219{2-[1-(3,5-Dimethyl-isoxazole-4-carbonyl)- 547 548 [M + H]⁺ +piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 220(2-{1-[4-(4-Chloro-benzenesulfonyl)-3- 722 723 [M + H]⁺ +methyl-thiophene-2-carbonyl]-piperidin-4-yl}-thiazol-4-yl)-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 221{2-[1-(4-Methyl-[1,2,3]thiadiazole-5- 550 551 [M + H]⁺ +carbonyl)-piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 222{2-[1-(Pyridine-3-carbonyl)-piperidin-4- 529 530 [M + H]⁺ +yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 223{2-[1-(2-Trifluoromethoxy-benzoyl)- 612 613 [M + H]⁺ +++piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 2243-Cyclopentyl-1-(4-{4-[4-(3- 548 549 [M + H]⁺ +trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl}-piperidin-1-yl)- propan-1-one 225[4-(3-Trifluoromethyl-phenyl)-piperazin-1- 618 619 [M + H]⁺ +yl]-{2-[1-(3,4,5-trimethoxy-benzoyl)-piperidin-4-yl]-thiazol-4-yl}-methanone 226{2-[1-(3-Dimethylamino-benzoyl)- 571 572 [M + H]⁺ ++piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 2292-(4-Fluoro-phenyl)-1-(4-{4-[4-(2- 511 523 [M + H]⁺ +methoxy-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl}-piperidin-1-yl)-ethanone 230{2-[1-(Furan-2-carbonyl)-piperidin-4-yl]- 518 519 [M + H]⁺ +thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone231 1-{4-[4-(4-Butyl-piperazine-1-carbonyl)- 472 473 [M + H]⁺ +thiazol-2-yl]-piperidin-1-yl}-2-(4-fluoro- phenyl)-ethanone 2372-(4-Fluoro-phenyl)-1-{4-[4-(4-pyridin-2- 493 494 [M + H]⁺ +yl-piperazine-1-carbonyl)-thiazol-2-yl]- piperidin-1-yl}-ethanone 2381-(4-{4-[4-(3-Chloro-phenyl)-piperazine-1- 526 527 [M + H]⁺ +carbonyl]-thiazol-2-yl}-piperidin-1-yl)-2- (4-fluoro-phenyl)-ethanone¹⁾The biological data refer to results obtained from the NF-κBinflammation assay. [“+” stands for 50-80% inhibition, “++” means 80-90%and “+++” stands for 90-100% inhibition]Examplary compounds of formula (Ia) of the present invention include,but are not limited to, the followings:

LC/(+)-ESI- Biological Cp. Name Mass MS: activity¹⁾ 744-{4-[4-(3-Trifluoromethyl-phenyl)- 619 620 [M + H]⁺ ++piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carboxylic acid(7-fluoro-2,3- dihydro-benzo[1,4]dioxin-5-yl)-amide 754-{4-[4-(3-Trifluoromethyl-phenyl)- 601 602 [M + H]⁺ ++piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carboxylic acid(2,3-dihydro- benzo[1,4]dioxin-6-yl)-amide 764-{4-[4-(3-Trifluoromethyl-phenyl)- 615 616 [M + H]⁺ ++piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carboxylic acid(5-methyl-2- trifluoromethyl-furan-3-yl)-amide 774-{4-[4-(3-Trifluoromethyl-phenyl)- 577 578 [M + H]⁺ +++piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carboxylic acid(2-thiophen-2- yl-ethyl)-amide 78 4-{4-[4-(3-Trifluoromethyl-phenyl)-509 510 [M + H]⁺ + piperazine-1-carbonyl]-thiazol-2-yl}-piperidine-1-carboxylic acid isopropylamide 794-{4-[4-(3-Trifluoromethyl-phenyl)- 627 628 [M + H]⁺ +++piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carboxylic acid (2-trifluoromethoxy-phenyl)-amide 80 4-{4-[4-(3-Trifluoromethyl-phenyl)-573 574 [M + H]⁺ + piperazine-1-carbonyl]-thiazol-2-yl}-piperidine-1-carboxylic acid (3-methoxy- phenyl)-amide 814-{4-[4-(3-Trifluoromethyl-phenyl)- 633 634 [M + H]⁺ ++piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carboxylic acid(3,4,5- trimethoxy-phenyl)-amide 1144-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 568 569 [M + H]⁺ +piperazine-1-carbonyl]-thiazol-2-yl}-piperidine-1-carbonyl)-benzonitrile 1344-{4-[4-(3-Trifluoromethyl-phenyl)- 543 544 [M + H]⁺ +piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carboxylic acidphenylamide 142 4-{4-[4-(3-Trifluoromethyl-phenyl)- 561 562 [M + H]⁺ ++piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carboxylic acid(3-fluoro- phenyl)-amide 143 4-{4-[4-(3-Trifluoromethyl-phenyl)- 561 562[M + H]⁺ + piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carboxylicacid (4-fluoro- phenyl)-amide ¹⁾The biological data refer to resultsobtained from the NF-κB inflammation assay. [“+” stands for 50-80%inhibition, “++” means 80-90% and “+++” stands for 90-100% inhibition]Examplary compounds of formula (Ib) of the present invention include,but are not limited to, the followings:

LC/(+)-ESI- Biological Cp. Name Mass MS: activity¹⁾ 1032-{5-Methyl-2-[1-(2-trifluoromethoxy- 640 641 [M + H]⁺ ++benzoyl)-piperidin-4-yl]-thiazol-4-yl}-1-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- ethanone 1281-[4-(3-Chloro-phenyl)-piperazin-1-yl]-2- 606 607 [M + H]⁺ +++{5-methyl-2-[1-(2-trifluoromethoxy-benzoyl)-piperidin-4-yl]-thiazol-4-yl}- ethanone ¹⁾The biological datarefer to results obtained from the NF-κB inflammation assay. [“+” standsfor 50-80% inhibition, “++” means 80-90% and “+++” stands for 90-100%inhibition]Examplary compounds of formula (Ic) of the present invention include,but are not limited to, the followings:

Biological Cp. Name Mass LC/(+)-ESI-MS: activity¹⁾ 150[1-(5-Chloro-2-methylamino-phenyl)-3,4- 654 655 [M + H]⁺ ++dihydro-1H-isoquinolin-2-yl]-{2-[1-(2-trifluoromethoxy-benzoyl)-piperidin-4-yl]- thiazol-4-yl}-methanone 1601-{4-[4-(6,7-Dihydroxy-3,4-dihydro-1H- 495 496 [M + H]⁺ +isoquinoline-2-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-2-(4-fluoro-phenyl)- ethanone 1611-{4-[4-(6,7-Dimethoxy-3,4-dihydro-1H- 523 524 [M + H]⁺ +isoquinoline-2-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-2-(4-fluoro-phenyl)- ethanone 1631-{4-[4-(3,4-Dihydro-1H-isoquinoline-2- 463 464 [M + H]⁺ +carbonyl)-thiazol-2-yl]-piperidin-1-yl}-2- (4-fluoro-phenyl)-ethanone232 1-{4-[4-(6,7-Dimethoxy-3-methyl-3,4- 537 538 [M + H]⁺ +dihydro-1H-isoquinoline-2-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-2-(4-fluoro- phenyl)-ethanone 2331-{4-[4-(6,7-Dihydroxy-1-methyl-3,4- 509 510 [M + H]⁺ +dihydro-1H-isoquinoline-2-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-2-(4-fluoro- phenyl)-ethanone 2341-{4-[4-(6,7-Dimethoxy-1-methyl-3,4- 537 538 [M + H]⁺ +dihydro-1H-isoquinoline-2-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-2-(4-fluoro- phenyl)-ethanone 2351-(4-{4-[1-(5-Chloro-2-methylamino- 602 603 [M + H]⁺ +phenyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-thiazol-2-yl}-piperidin-1-yl)-2- (4-fluoro-phenyl)-ethanone¹⁾The biological data refer to results obtained from the NF-κBinflammation assay. [“+” stands for 50-80% inhibition, “++” means 80-90%and “+++” stands for 90-100% inhibition]Examplary compounds of formula (II) of the present invention include,but are not limited to, the followings:

LC/(+)-ESI- Biological Cp. Name Mass MS: activity¹⁾ 3N-{4-[4-(4-Fluoro-phenyl)-piperazine-1- 494 495 [M + H]⁺ ++carbonyl]-thiazol-2-yl}-2-trifluoromethoxy- benzamide 5N-[5-(4-Pyrimidin-2-yl-piperazine-1- 478 479 [M + H]⁺ +carbonyl)-thiazol-2-yl]-2-trifluoromethoxy- benzamide 152-Methoxy-N-{4-[4-(3-trifluoromethyl- 490 491 [M + H]⁺ +++phenyl)-piperazine-1-carbonyl]-thiazol-2- yl}-benzamide 163-Fluoro-4-trifluoromethyl-N-(1-{4-[4-(3- 643 644 [M + H]⁺ ++trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl}piperidin-4- ylmethyl)-benzamide 173-Cyclopentyl-N-(1-{4-[4-(3- 577 578 [M + H]⁺ ++trifluoromethyl-phenyl)-piperazine-1- carbonyl]-thiazol-2-yl}-piperidin-4ylmethyl)-propionamide 18 2-Trifluoromethoxy-N-(1-{4-[4-(3- 641 642[M + H]⁺ ++ trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl}-piperidin- 4ylmethyl)-benzamide 194-Cyano-N-(1-{4-[4-(3-trifluoromethyl- 582 583 [M + H]⁺ ++phenyl)-piperazine-1-carbonyl]-thiazol-2-yl}-piperidin-4-ylmethyl)-benzamide 20[4-(3-Trifluoromethyl-phenyl)-piperazin-1- 569 570 [M + H]⁺ ++yl]-{2-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-thiazol-4-yl}-methanone 21{2-[4-(4-Trifluoromethoxy-phenyl)- 585 586 [M + H]⁺ +piperazin-1-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 22{2-[4-(2-Trifluoromethoxy-benzyl)- 599 600 [M + H]⁺ +++piperazin-1-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 23{2-[4-(4-Bromo-benzyl)-piperazin-1-yl]- 593 594 [M + H]⁺ +++thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone24 {2-[4-(3-Trifluoromethoxy-benzyl)- 599 600 [M + H]⁺ +++piperazin-1-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 322-Trifluoromethoxy-N-{4-[4-(3- 544 545 [M + H]⁺ +++trifluoromethyl-phenyl)-piperazine-1- carbonyl]-thiazol-2-yl}-benzamide33 3-Cyclopentyl-N-{4-[4-(3-trifluoromethyl- 480 481 [M + H]⁺ +++phenyl)-piperazine-1-carbonyl]-thiazol-2- yl}-propionamide 343-Fluoro-4-trifluoromethyl-N-{4-[4-(3- 546 547 [M + H]⁺ +++trifluoromethyl-phenyl)-piperazine-1- carbonyl]-thiazol-2-yl}-benzamide37 3-Cyclopentyl-1-(4-{4-[4-(3- 549 550 [M + H]⁺ +++trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl}-piperazin-1-yl)- propan-1-one 38{2-[4-(2-Methoxy-benzoyl)-piperazin-1- 559 560 [M + H]⁺ +++yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 39 {2-[4-(2-Trifluoromethoxy-benzoyl)-613 614 [M + H]⁺ +++ piperazin-1-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 41N-{4-[4-(3,4-Dichloro-phenyl)-piperazine- 544 545 [M + H]⁺ +++1-carbonyl]-thiazol-2-yl}-2- trifluoromethoxy-benzamide 44N-{4-[4-(2-Methoxy-phenyl)-piperazine-1- 506 507 [M + H]⁺ ++carbonyl]-thiazol-2-yl}-2-trifluoromethoxy- benzamide 551-(2-Trifluoromethoxy-phenyl)-3-{4-[4-(3- 559 560 [M + H]⁺ +++trifluoromethyl-phenyl)-piperazine-1- carbonyl]-thiazol-2-yl}-urea 58N-[4-(4-Benzhydryl-piperazine-1- 566 567 [M + H]⁺ ++carbonyl)-thiazol-2-yl]-2-trifluoromethoxy- benzamide 59{2-[4-(3,5-Bis-trifluoromethyl-benzoyl)- 665 666 [M + H]⁺ +piperazin-1-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 60{2-[4-(3-Fluoro-4-trifluoromethyl- 615 616 [M + H]⁺ +++benzoyl)-piperazin-1-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 614-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 554 555 [M + H]⁺ +++piperazine-1-carbonyl]-thiazol-2-yl}-piperazine-1-carbonyl)-benzonitrile 624-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 540 541 [M + H]⁺ +++piperazine-1-carbonyl]-thiazol-2-yl}-piperazine-1-ylmethyl)-benzonitrile 634-{4-[4-(3-Trifluoromethyl-phenyl)- 525 526 [M + H]⁺ ++piperazine-1-carbonyl]-thiazol-2-yl}- piperazine-1-carboxylic acidtert-butyl ester 64 (2-Piperazin-1-yl-thiazol-4-yl)-[4-(3- 425 426 [M +H]⁺ + trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 65{2-[4-(2-Methoxy-phenyl)-piperazin-1-yl]- 531 532 [M + H]⁺ ++thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone66 1-[4-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 543 544 [M + H]⁺ ++piperazine-1-carbonyl]-thiazol-2-yl}- piperazin-1-yl)-phenyl]-ethanone67 [4-(3-Trifluoromethyl-phenyl)-piperazin-1- 569 570 [M + H]⁺ +yl]-{2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-thiazol-4-yl}-methanone 68[2-(4-Phenyl-piperazin-1-yl)-thiazol-4-yl]- 501 502 [M + H]⁺ +[4-(3-trifluoromethyl-phenyl)-piperazin-1- yl]-methanone 69{2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]- 519 520 [M + H]⁺ ++thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone71 (4-Benzhydryl-piperazin-1-yl)-[2-(4- 537 538 [M + H]⁺ +++benzyl-piperazin-1-yl)-thiazol-4-yl]- methanone 72[2-(4-Benzyl-piperazin-1-yl)-thiazol-4-yl]- 515 516 [M + H]⁺ +++[4-(3-trifluoromethyl-phenyl)-piperazin-1- yl]-methanone 993-Fluoro-4-trifluoromethyl-N-(1-{4-[4-(3- 642 643 [M + H]⁺ +trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl}-piperidin-4- ylmethyl)-benzamide 1003-Cyclopentyl-N-(1-{4-[4-(3- 576 577 [M + H]⁺ +trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl}-piperidin-4- ylmethyl)-propionamide 1012-Trifluoromethoxy-N-(1-{4-[4-(3- 640 641 [M + H]⁺ +trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl}-piperidin-4- ylmethyl)-benzamide 1024-Cyano-N-(1-{4-[4-(3-trifluoromethyl- 581 582 [M + H]⁺ +phenyl)-piperazine-1-carbonyl]-thiazol-2-yl}-piperidin-4-ylmethyl)-benzamide 241{2-[1-(2,6-Dimethoxy-pyrimidin-4-yl)- 576 577 [M + H⁺] ++piperidin-4-yl]-5-methoxy-oxazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 242{2-[1-(4,6-Dimethoxy-[1,3,5]triazin-2-yl)- 577 578 [M + H⁺] ++piperidin-4-yl]-5-methoxy-oxazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 243{2-[1-(2,6-Dimethoxy-pyrimidin-4-yl)- 616 617 [M + H⁺] ++piperidin-4-yl]-5-methoxy-oxazol-4-yl}-[4-(5-trifluoromethyl-benzotriazol-1-yl)- piperidin-1-yl]-methanone 244{2-[1-(4,6-Dimethoxy-[1,3,5]triazin-2-yl)- 617 618 [M + H⁺] ++piperidin-4-yl]-5-methoxy-oxazol-4-yl}-[4-(5-trifluoromethyl-benzotriazol-1-yl)- piperidin-1-yl]-methanone 2454-(4-{4-[4-(5-Trifluoromethyl-benzotriazol- 580 581 [M + H]+ ++1-yl)-piperidine-1-carbonyl]-thiazol-2-yl}-piperazin-1-yl-methyl)-benzonitrile 246(2-Morpholin-4-yl-oxazol-4-yl)-[4-(3- 410 411 [M + H]+ +trifluoromethyl-phenyl)-piperazin-1-yl]- methanone ¹⁾The biological datarefer to results obtained from the NF-κB inflammation assay. [“+” standsfor 50-80% inhibition, “++” means 80-90% and “+++” stands for 90-100%inhibition]Examplary compounds of formula (III) of the present invention include,but are not limited to, the followings:

LC/(+)-ESI- Biological Cp. Name Mass MS: activity¹⁾ 12-Morpholin-4-yl-thiazole-4-carboxylic 357 358 [M + H]⁺ + acid(5,6-dimethyl-1H-benzoimidazol-2- yl)-amide 22-[3-(2-Trifluoromethoxy-phenyl)-ureido]- 462 463 [M + H]⁺ +thiazole-4-carboxylic acid (1H- benzoimidazol-2-yl)-amide 42-(2-Fluoro-benzoylamino)-thiazole-4- 409 410 [M + H]⁺ + carboxylic acid(5,6-dimethyl-1H- benzoimidazol-2-yl)-amide 6N-{4-[N′-(1H-Benzoimidazol-2-yl)- 441 442 [M + H]⁺ ++guanidinocarbonyl]-thiazol-2-yl}-3,4- difluoro-benzamide 7N-{4-[N′-(1H-Benzoimidazol-2-yl)- 423 424 [M + H]⁺ ++guanidinocarbonyl]-thiazol-2-yl}-4-fluoro- benzamide 8N-{4-[N′-(1H-Benzoimidazol-2-yl)- 473 474 [M + H]⁺ +++guanidinocarbonyl]-oxazol-2-yl}-2- trifluoromethoxy-benzamide 92-(2-Trifluoromethoxy-benzoylamino)- 453 454 [M + H]⁺ +thiazole-4-carboxylic acid (4- dimethylamino-[1,3,5]triazin-2-yl)-amide10 N-{4-[N′-(1H-Benzoimidazol-2-yl)- 483 484 [M + H]⁺ ++guanidinocarbonyl]-thiazol-2-yl}-4-bromo- benzamide 11N-{4-[N′-(1H-Benzoimidazol-2-yl)- 435 436 [M + H]⁺ ++guanidinocarbonyl]-thiazol-2-yl}-2- methoxy-benzamide 12N-{4-[N′-(1H-Benzoimidazol-2-yl)- 489 490 [M + H]⁺ +++guanidinocarbonyl]-thiazol-2-yl}-2- trifluoromethoxy-benzamide 13N-(1H-Benzoimidazol-2-yl)-N′-{2-[4-(2- 558 559 [M + H]⁺ +trifluoromethoxy-benzoyl)-piperazin-1-yl]-thiazole-4-carbonyl}-guanidine 14 N-(1H-Benzoimidazol-2-yl)-N′-[2-(2,3-420 421 [M + H]⁺ + dihydro-benzo[1,4]dioxin-2-yl)-thiazole-4-carbonyl]-guanidine 25 2-(2-Trifluoromethoxy-benzoylamino)- 475 476 [M +H]⁺ +++ thiazole-4-carboxylic acid (5,6-dimethyl-1H-benzoimidazol-2-yl)-amide 26 2-(3-Fluoro-4-trifluoromethyl- 536 537[M + H]⁺ +++ benzoylamino)-oxazole-4-carboxylic acid ethyl ester 27N-{4-[N′-(1H-Benzoimidazol-2-yl)- 475 476 [M + H]⁺ +++guanidinocarbonyl]-oxazol-2-yl}-3-fluoro- 4-trifluoromethyl-benzamide 30N-(1H-Benzoimidazol-2-yl)-N′-[2-(4- 460 461 [M + H]⁺ +++benzyl-piperazin-1-yl)-thiazole-4- carbonyl]-guanidine 312-(2-Trifluoromethoxy-benzoylamino)- 447 448 [M + H]⁺ +++thiazole-4-carboxylic acid (1H- benzoimidazol-2-yl)-amide 36N-(1H-Benzoimidazol-2-yl)-N′-{2-[1-(2- 557 558 [M + H]⁺ +++trifluoromethoxy-benzoyl)-piperidin-4-yl]-thiazole-4-carbonyl}-guanidine 40 2-(2-Trifluoromethoxy-benzoylamino)-459 460 [M + H]⁺ +++ oxazole-4-carboxylic acid (5,6-dimethyl-1H-benzoimidazol-2-yl)-amide 42 2-(2-Trifluoromethoxy-benzoylamino)- 562563 [M + H]⁺ +++ thiazole-4-carboxylic acid [6-(4-methyl-piperazin-1-yl)-benzothiazol-2-yl]-amide 432-(2-Trifluoromethoxy-benzoylamino)- 492 493 [M + H]⁺ +++thiazole-4-carboxylic acid (5-nitro-1H- benzoimidazol-2-yl)-amide 45N-{4-[N′-(1H-Benzoimidazol-2-yl)- 487 488 [M + H]⁺ +++guanidinocarbonyl]-thiazol-2-yl}-2- cyclohexyl-benzamide 462-(2-Trifluoromethoxy-benzoylamino)- 461 462 [M + H]⁺ +++thiazole-4-carboxylic acid (1-methyl-1H- benzoimidazol-2-yl)-amide 472-(2-Trifluoromethoxy-benzoylamino)- 553 554 [M + H]⁺ +++thiazole-4-carboxylic acid [5-(propane-1-sulfonyl)-1H-benzoimidazol-2-yl]-amide 49N-(1H-Benzoimidazol-2-yl)-N′-(2- 371 372 [M + H]⁺ +++morpholin-4-yl-thiazole-4-carbonyl)- guanidine 51N-{4-[N′-(1H-Benzoimidazol-2-yl)- 473 474 [M + H]⁺ +++guanidinocarbonyl]-thiazol-2-yl}-4- trifluoromethyl-benzamide 522-[1-(2-Trifluoromethoxy-benzoyl)- 621 622 [M + H]⁺ +++piperidin-4-yl]-thiazole-4-carboxylic acid[5-(propane-1-sulfonyl)-1H-benzoimidazol- 2-yl]-amide 53N-{4-[N′-(1H-Benzoimidazol-2-yl)- 491 492 [M + H]⁺ +++guanidinocarbonyl]-thiazol-2-yl}-2-fluoro- 4-trifluoromethyl-benzamide54 1-{4-[N′-(1H-Benzoimidazol-2-yl)- 504 505 [M + H]⁺ +++guanidinocarbonyl]-thiazol-2-yl}-3-(2- trifluoromethoxy-phenyl)-urea 56N-{4-[N′-(1H-Benzoimidazol-2-yl)- 491 492 [M + H]⁺ +++guanidinocarbonyl]-thiazol-2-yl}-3-fluoro- 4-trifluoromethyl-benzamide57 N-{4-[N′-(1H-Benzoimidazol-2-yl)- 441 442 [M + H]⁺ +++guanidinocarbonyl]-thiazol-2-yl}-2,6- difluoro-benzamide 91N-(1H-Benzoimidazol-2-yl)-N′-(2- 371 372 [M + H]⁺ +morpholin-4-yl-thiazole-4-carbonyl)- guanidine 250N-(1H-Benzoimidazol-2-yl)-N′-{2-[1-(4- 484 485 [M + H]+ ++cyano-benzyl)-piperidin-4-yl]-thiazole-4- carbonyl}-guanidine 251N-Benzothiazol-2-yl-N′-{2-[1-(4-cyano- 501 502 [M + H]+ ++benzyl)-piperidin-4-yl]-thiazole-4- carbonyl}-guanidine 252N-(1H-Benzoimidazol-2-yl)-N′-{2-[4-(4- 485 485 [M + H]+ +++cyano-benzyl)-piperazin-1-yl]-thiazole-4- carbonyl}-guanidine 253N-{2-[4-(4-Cyano-benzyl)-piperazin-1-yl]- 466 467 [M + H]+ ++thiazole-4-carbonyl}-N′-(4-methyl-thiazol- 2-yl)-guanidine 254N-(4-Methyl-thiazol-2-yl)-N′-(2-morpholin- 352 353 [M + H]+ +4-yl-thiazole-4-carbonyl)-guanidine 255 N-(1H-Benzoimidazol-2-yl)-N′-(2-371 372 [M + H]+ +++ morpholin-4-yl-thiazole-4-carbonyl)- guanidine 256N-Benzothiazol-2-yl-N′-(2-morpholin-4-yl- 388 389 [M + H]+ +++thiazole-4-carbonyl)-guanidine 257 N-(1H-Benzoimidazol-2-yl)-N′-(2- 355356 [M + H]+ ++ morpholin-4-yl-oxazole-4-carbonyl)- guanidine 258N-Benzooxazol-2-yl-N′-(2-morpholin-4-yl- 372 373 [M + H]+ ++thiazole-4-carbonyl)-guanidine 259N-(2-Morpholin-4-yl-thiazole-4-carbonyl)- 417 418 [M + H]+ ++N′-(5-nitro-benzooxazol-2-yl)-guanidine 260N-(5-Methyl-benzooxazol-2-yl)-N′-(2- 386 387 [M + H]+ +morpholin-4-yl-thiazole-4-carbonyl)- guanidine 261N-(5-Chloro-benzooxazol-2-yl)-N′-(2- 406 407 [M + H]+ ++morpholin-4-yl-thiazole-4-carbonyl)- guanidine 262N-{2-[1-(4-Cyano-benzyl)-piperidin-4-yl]- 465 466 [M + H]+ +thiazole-4-carbonyl}-N′-(4-methyl-thiazol- 2-yl)-guanidine 263N-(6-Chloro-1H-benzoimidazol-2-yl)-N′- 591 592 [M + H]+ +++{2-[1-(2-trifluoromethoxy-benzoyl)-piperidin-4-yl]-thiazole-4-carbonyl}- guanidine 264N-(5,6-Dichloro-1H-benzoimidazol-2-yl)- 625 626 [M + H]+ ++N′-{2-[1-(2-trifluoromethoxy-benzoyl)-piperidin-4-yl]-thiazole-4-carbonyl}- guanidine 2652-Morpholin-4-yl-thiazole-4-carboxylic 490 491 [M + H]+ acid[4-(5-trifluoromethyl-benzothiazol-2- yl)-phenyl]-amide 2662-Morpholin-4-yl-thiazole-4-carboxylic 423 424 [M + H]+ acid(5-benzothiazol-2-yl-pyridin-2-yl)- amide 2672-Morpholin-4-yl-thiazole-4-carboxylic 440 441 [M + H]+ acid(4-benzothiazol-2-yl-2-fluoro-phenyl)- amide 2682-Morpholin-4-yl-thiazole-4-carboxylic 506 507 [M + H]+ acid(4-benzothiazol-2-yl-2-trifluoromethoxy- phenyl)-amide 2692-(1-Furo[2,3-c]pyridin-4-yl-piperidin-4- 548 549 [M + H]+yl)-thiazole-4-carboxylic acid (5-benzoyl- 1H-benzoimidazol-2-yl)-amide270 2-[1-(4,6-Dimethoxy-[1,3,5]triazin-2-yl)- 570 571 [M + H]+piperidin-4-yl]-thiazole-4-carboxylic acid(5-benzoyl-1H-benzoimidazol-2-yl)-amide 2712-[1-(4,6-Dimethoxy-[1,3,5]triazin-2-yl)- 501 502 [M + H]+piperidin-4-yl]-thiazole-4-carboxylic acid(5-fluoro-benzothiazol-2-yl)-amide 2722-[1-(4-Cyano-benzyl)-piperidin-4-yl]- 546 547 [M + H⁺] ++thiazole-4-carboxylic acid (5-benzoyl-1H- benzoimidazol-2-yl)-amide 2732-(1-Thieno[3,2-d]pyrimidin-4-yl- 565 566 [M + H⁺] ++piperidin-4-yl)-thiazole-4-carboxylic acid(5-benzoyl-1H-benzoimidazol-2-yl)-amide 2742-[1-(4,6-Dimethoxy-[1,3,5]triazin-2-yl)- 570 571 [M + H⁺] +++piperidin-4-yl]-thiazole-4-carboxylic acid(5-benzoyl-1H-benzoimidazol-2-yl)-amide 2752-[1-(6-Trifluoromethyl-pyrimidin-4-yl)- 577 578 [M + H⁺] ++piperidin-4-yl]-thiazole-4-carboxylic acid(5-benzoyl-1H-benzoimidazol-2-yl)-amide 2762-[1-(4-Cyano-benzyl)-piperidin-4-yl]- 486 487 [M + H]+ +thiazole-4-carboxylic acid (5-ethoxy-1H- benzoimidazol-2-yl)-amide 2772-[1-(4-Cyano-benzyl)-piperidin-4-yl]- 476 477 [M + H]+ ++thiazole-4-carboxylic acid (5-chloro-1H- benzoimidazol-2-yl)-amide 2782-[1-(4-Cyano-benzyl)-piperidin-4-yl]- 510 511 [M + H]+ ++thiazole-4-carboxylic acid (5,6-dichloro- 1H-benzoimidazol-2-yl)-amide¹⁾The biological data refer to results obtained from the NF-κBinflammation assay. [“+” stands for 50-80% inhibition, “++” means 80-90%and “+++” stands for 90-100% inhibition]

Proteasome Assay:

The chymotryptic activity of the 20S proteasome (Immatics, Tübingen) wasdetermined using a Tecan Ultra plate reader and Suc-LLVT-AMC assubstrate (Bachem). In the wells of a black 96 well polypropylene plate,2 μl of the respective inhibitor dissolved in DMSO were mixed with 50 μlsubstrate solution (25 mM HEPES pH 7.5 at 20° C., 0.5 mM EDTA andSuc-LLVT-AMC (in the appropriate concentration) and the reaction wasinitiated by adding 150 μl proteasome solution (1.3 μg/ml 20S proteasomein 25 mM HEPES pH 7.5 at 20° C., 0.5 mM EDTA, 0.033% (w/v) SDS).Substrate hydrolysis was followed by fluorescence spectroscopy(excitation wavelength: 360 nm; emission wavelength: 465 nm) for 20 minat 30° C. and initial velocities were calculated and expressed as changein relative fluorescence units (RFU) per second.

For the determination of the IC₅₀ values (concentration of inhibitorrequired for 50% inhibition) at least four different inhibitorconcentrations were applied. Each data point was recorded intriplicates. Curves were fitted with the a suitable program.

The Compounds have average activities between 1 and 30 μM.

T-Lymphocyte Proliferation Assay:

Inhibition of Stimulated Peripheral Blood Monocytes (PBMC).

PBMCs were isolated from the blood of healthy volunteers with the helpof ACCUSPIN™ System Histopaque®-1077 tubes, washed and resuspended with10⁶ cells/ml in Dulbecco's modified eagles medium, containing 10% fetalcalf serum and 2 mM Glutamine.

The cells were stimulated with 2 μg/ml phytohemoagglutinin in thepresence of test compound or blank vehicle for 72 h. 4 h prior to theend of the incubation period, 5-bromo-2′-desoxyuridine (BrdU) was addedto label the proliferating cells. After the incubation, the cells wereseparated by centrifugation and the culture supernatant removed.Incorporated BrdU was quantified with the help of an enzyme-linkedimmunosorbent assay.

For the determination of the IC₅₀ values (concentration of inhibitorrequired for 50% inhibition) at least four different inhibitorconcentrations were applied. Each data point was recorded intriplicates. Curves were fitted with the a suitable program.

Influence of Compounds According to the Invention on Proliferation ofT-Cells

Compounds according to Examples 1-24 resulted in an inhibition of morethan 50% compared to control experiments.

The average EC₅₀ of the compounds were between 3 and 40 μM.

Thus, the compounds of formula I are suitable for treating inflammatorydiseases or diseases associated with Tcells.

Inhibition of NF-κB-Induced Inflammation:

For the determination of anti-inflammatory activity of the compounds thePRINCESS® NINA Instant Assay from Cell Culture Service GmBH was used.This assay is based on recombinant A549-NF-κB-SEAP reporter cellspreseeded in 96-well flat bottom plates. As the transfected reportergenfor SEAP (secreted embryonic alkaline phosphatase) is undertranscriptional control of a NF-κB-responsive element, the expression ofthis reporter is activated upon stimulation with TNF-α. SEAP secretioninto the culture supernatant can be detected by the chemiluminescentsubstrate CSPD®. Test compounds that inhibit the NF-κB activation showreduced SEAP activity and reduced luminescent readout.

Following 18 h of reactivation at 37° C., 5% CO₂ and 90% relativehumidity, the cells were incubated with 0.01 up to 100 μM of testcompound for 4.5 h before stimulation with 2 ng/ml TNF-α. Afterstimulation with TNF-α for 22 h endogenous phosphatases were inactivatedand CSPD® substrate was supplied for 40 min. SEAP activity then wasquantified by measuring luminescence as relative light units (RLU) usinga Tecan Ultra reader. Each data point was recorded in quadruplicates andEC50 values were calculated via fitting function and the Microsoft ExcelSolver.

1. A compound of the general formula (II) or pharmaceutically acceptablesalts thereof with an acid or a base, or pharmaceutically acceptableprodrugs or a stereoisomer thereof,

wherein R¹ is —C(O)R⁷, —C(O)CHR⁷R⁸, —C(O)NR⁷R⁸, —C(O)OR⁷, —R⁷C(O)R⁸,—C(S)R⁷; R² is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl,hydroxyalkyl, alkylamino, hydroxyalkylamino, heteroaryl, or R¹ and R²together with the N-atom or the C-atom to which they are attached form a3 to 8 membered saturated or at least partially unsaturated monocyclicor polycyclic ring system, wherein at least one or more of the carbonatoms in the ring is a heteroatom selected from O, N, and S, and thering can be substituted by one or more R⁹; R³ is H, —C(O)NR^(a)R^(b),halogen, alkyl, haloalkyl, aryl, heteroaryl, OH, SH, NR^(4′)OR^(5′),NH₂, hydroxyalkylamino, alkylamino, alkoxy, cycloalkyl,heterocycloalkyl, hydroxyalkyl, or haloalkyloxy; R^(a) is H, halogen,alkyl, —C(NR⁷)NR^(7′)R⁸, —(CH₂)_(p)aryl, —(CH₂)_(p)NR⁷R⁸, —C(O)NR⁷R⁸,—N═CR⁷R⁸, —NR⁷C(O)R⁸, cycloalkyl, heterocycloalkyl, haloalkyl,hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; R^(b)independently represents H, —CN, —OH, —SH, —CO₂R^(4′), —C(O)R^(4′),—SO₂NR^(4′), —NR^(4′)R^(5′), —C(O)NR⁷R⁸, —SO₂-alkyl, —SO₂R^(4′),SO₃R^(4′), —N═CR^(4′)R^(5′), —NR^(4′)C(O)R^(4″), —NR^(4′)—CO-haloalkyl,—NO₂, —NR^(4′)—SO₂-haloalkyl, —NR^(4′)—SO₂-alkyl, —NR^(4′)—CO-alkyl,—NR^(4′)(CH₂)_(p)heterocycle, alkyl, cycloalkyl, alkylamino, alkoxy,alkylthio, halogen, haloalkyl, haloalkyloxy,—O(CH₂)_(p)[O(CH₂)_(p)]_(q)OCH₃, —C(NR^(4″))NR^(4′)benzimidazolyl,—C(NR^(4″))NR^(4′)benzthiazolyl, —C(NR^(4″))NR^(4′)benzoxazolyl,hydroxyalkyl, hydroxy-alkylamino, aryl, heterocycloalkyl, or heteroaryl;R⁶ is halogen, —C(O)R⁷, —C(O)CHR⁷R⁸, —C(O)NR⁷R⁸, —C(O)OR⁷, —R⁷C(O)R⁸,—C(S)R⁷, —C(NR⁷)NR^(7′)R⁸, —(CH₂)_(p)aryl, —(CH₂)_(p)NR⁷R⁸, —C(O)NR⁷R⁸,—N═CR⁷R⁸, —NR⁷C(O)R⁷, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl,hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; R⁷,R^(7′), R⁸ independently are H, halogen, alkyl, cycloalkyl,heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino,alkylamino, —NHaryl, heteroaryl, or aryl; A is CO or SO₂; X is NR^(2′),O, or S; Y is N, CR^(2′) or if Y is O then R⁶ is absent; Z is N orCR^(2′); if Z is CH then X is O or NR^(2′); R^(2′) is H, alkyl,—C(O)R^(b), cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl,hydroxyalkylamino, alkylamino, heteroaryl, or aryl; n is 0 to 2; p is 1to 6; q is 1 to 6; R⁹ independently represents H, —CN, —OH, —SH,—CO₂R^(4′), —C(O)R^(4a), —C(O)NR⁷R⁸, —SO₂NR^(4′), —NR^(4′)R^(5′),—SO₂-alkyl, —SO₂R^(4′), SO₃R^(4′), —N═CR^(4′)R^(5′), —NR^(4′)C(O)R^(4″),—NR^(4′)—CO-haloalkyl, —NO₂, —NR^(4′)—SO₂-haloalkyl, —NR^(4′)—SO₂-alkyl,—NR^(4′)—CO-alkyl, —NR^(4′)(CH₂)_(p)heteroaryl, alkyl, cycloalkyl,heterocycloalkyl, alkylamino, alkoxy, alkylthio, halogen, haloalkyl,haloalkyloxy, hydroxyalkylamino, hydroxyalkyl, hydroxycycloalkyl, aryl,—O(CH₂)_(p)[O(CH₂)_(p)]_(q)OCH₃, —C(NR^(4″))NR^(4′)benzimidazolyl,—C(NR^(4″))NR^(4′)benzthiazolyl, —C(NR^(4″))NR^(4′)benzoxazolyl,—(CH₂)_(p)NR⁷COR⁸, or heteroaryl; R^(4′), R^(4″), R^(5′) independentlyare H, halogen, alkyl, —C(NR⁷)NR^(7′)R⁸, —(CH₂)_(p)aryl,—(CH₂)_(p)NR⁷R⁸, —C(O)NR⁷R⁸, —N═CR⁷R⁸, —NR⁷C(O)R⁸, cycloalkyl,heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino,alkylamino, heteroaryl, or aryl; R^(4a) is H, C₁-C₆-alkyl,C₂-C₆-alkenyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino,alkylamino, —C(NR⁷)NR^(7′)R⁸, —(CH₂)_(p)aryl, —CH₂)_(p)NR⁷R⁸,—C(O)NR⁷R⁸, —N═CR⁷R⁸, —NR⁷C(O)R⁸, halogen, heteroaryl, or aryl; whereina C₁-C₆-alkyl group, if not stated otherwise, denotes a linear orbranched C₁-C₆-alkyl, optionally substituted by one or more substituentsR′; a C₂-C₆-alkenyl group, if not stated otherwise, denotes a linear orbranched C₂-C₆-alkenyl, optionally substituted by one or moresubstituents R′; an alkyl group, if not stated otherwise, denotes alinear or branched C₁-C₆-alkyl, optionally substituted by one or moresubstituents R′; R′ is independently H, —CO₂R″, —CONHR″, —CR″O, —SO₂NR″,—NR″—CO-haloalkyl, —NO₂, —NR″—SO₂-haloalkyl, —NR″—SO₂-alkyl, —SO₂-alkyl,—NR″—CO-alkyl, —CN, alkyl, cycloalkyl, alkylamino, alkoxy, —OH, —SH,alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl,haloalkyloxy, aryl, or heteroaryl; R″ is independently H, haloalkyl,hydroxyalkyl, alkyl, cycloalkyl, aryl, or heteroaryl; a heterocycledenotes a heterocycloalkyl group or a heteroaryl group; a cycloalkylgroup denotes a non-aromatic ring system containing three to eightcarbon atoms, optionally substituted by one or more substituents R′,wherein R′ is as defined above; a heterocycloalkyl group denotes anon-aromatic ring system containing two to ten carbon atoms and at leastone heteroatom selected from O, N, and S, optionally substituted by oneor more substituents R′, wherein R′ is as defined above; an alkoxy groupdenotes an O-alkyl group, the alkyl group being as defined above; analkylthio group denotes an S-alkyl group, the alkyl group being asdefined above; an haloalkyl group denotes an alkyl group which issubstituted by one to five halogen atoms, the alkyl group being asdefined above; a hydroxyalkyl group denotes an HO-alkyl group, the alkylgroup being as defined above; an haloalkyloxy group denotes an alkoxygroup which is substituted by one to five halogen atoms, the alkyl groupbeing as defined above; a hydroxyalkylamino group denotes an(HO-alkyl)₂-N— group or HO-alkyl-NH— group, the alkyl group being asdefined above; an alkylamino group denotes an HN-alkyl or N-dialkylgroup, the alkyl group being as defined above; a halogen group isfluorine, chlorine, bromine, or iodine; an aryl group denotes anaromatic group having five to fifteen carbon atoms, which can besubstituted by one or more substituents R′, wherein R′ is as definedabove; a heteroaryl group denotes a 5- to 10-membered aromaticheterocyclic group which contains at least one heteroatom selected fromO, N, and S, wherein the heterocyclic group may be fused to another ringand the heterocyclic group or the fused ring can both be substitutedindependently by one or more substituents R′, wherein R′ is as definedabove.
 2. The compound according to claim 1, wherein: R³ is H; X is S; Ais CO; n is 1; and r is
 1. 3. A composition containing a compoundaccording to claim 1 or claim 2 and a pharmaceutically acceptablecarrier or diluent.
 4. A method for the treatment or prevention of adisease characterized by hyperproliferation of cells, wherein saidmethod comprises administering a compound according to claim 1 or claim2 to a patient in need thereof.
 5. A method for the treatment orprevention of a disease resulting from ischemia and/or reperfusioninjury of organs and/or of parts of the body selected from the groupcomprising heart, brain, peripheral limb, kidney, liver, spleen andlung, and/or wherein the endothelial dysfunction is associated withdiseases selected from a group comprising infarctions such as myocardialinfarction and critical limb ischemia, and/or wherein the endothelialdysfunction is associated with diseases selected from the groupcomprising ischemic diseases, myocardial infarction and ischemicdiseases of organs, wherein said method comprises administering acompound according to claim 1 or claim 2 to a patient in need thereof.6. A method for the treatment or prevention of a neurological diseasesor disorders selected from the group comprising Alzheimer's disease,Parkinson's disease, Creutzfeld-Jacob Disease, Lewy Body Dementia,amyotrophic lateral sclerosis, stroke, epilepsy, multiple sclerosis,myasthenia gravis, Huntington's Disease, Down's Syndrome, nervedeafness, and Meniere's disease, wherein said method comprisesadministering a compound according to claim 1 or claim 2 to a patient inneed thereof.
 7. A method for the treatment or prevention of diseasesthat are caused by protozoal infestations in humans and animals, bybacteria, viruses or proteinaceous agents, wherein said method comprisesadministering a compound according to claim 1 or claim 2 to a patient inneed thereof.
 8. A method for the treatment or prevention of diseasecharacterized by hyperproliferation of cells, wherein the disease isselected from the group consisting of psoriasis, atopic dermatitis,alopecia areata, alopecia totalis, alopecia subtotalis, alopeciauniversalis, alopecia diffusa, lupus erythematodes of the skin, lichenplanus, dermatomyostis of the skin, atopic eczema, morphea,sklerodermia, psoriasis vulgaris, psoriasis capitis, psoriasis guttata,psoriasis inversa, alopecia areata ophiasis-type, androgenetic alopecia,allergic contact eczema, irritative contact eczema, contact eczema,pemphigus vulgaris, pemphigus foliaceus, pemphigus vegetans, scarringmucosal pemphigoid, bullous pemphgoid, mucous pemphigoid, dermatitis,dermatitis herpetiformis duhring, urticaria, necrobiosis lipoidica,erythema nodosum, lichen vidal, prurigo simplex, prurigo nodularis,prurigo acuta, linear IgA dermatosis, polymorphic light dermatoses,erythema solaris, lichen sclerosus et atrophicans, exanthema of theskin, drug exanthema, purpura chronica progressiva, dihidrotic ekzema,Ekzema, fixed drug exanthema, photoallergic skin reaction, lichensimplex eriorale, dermatitis and “Graft versus Host-Disease”, acne,rosacea, scarring, keloids, vitiligo, actinic keratoses, hyperkeratoseslike epidermolytic hyperkeratosis, Hyperkeratosis Lenticularis Perstans,Keratosis pilaris and Ichthyoses, wherein said method comprisesadministering a compound according to claim 1 or claim 2 to a patient inneed thereof.
 9. A method for the treatment or prevention of diseasecharacterized by hyperproliferation of cells, wherein the disease isselected from the group consisting of hematological or solid tumors,wherein said method comprises administering a compound according toclaim 1 or claim 2 to a patient in need thereof.